CN110114074A - For treating or preventing the coagulation factor substitute products of bleeding - Google Patents
For treating or preventing the coagulation factor substitute products of bleeding Download PDFInfo
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- CN110114074A CN110114074A CN201880005539.2A CN201880005539A CN110114074A CN 110114074 A CN110114074 A CN 110114074A CN 201880005539 A CN201880005539 A CN 201880005539A CN 110114074 A CN110114074 A CN 110114074A
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- PYIHTIJNCRKDBV-UHFFFAOYSA-L trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;dichloride Chemical compound [Cl-].[Cl-].C[N+](C)(C)CCCCCC[N+](C)(C)C PYIHTIJNCRKDBV-UHFFFAOYSA-L 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 208000016794 vitamin K deficiency hemorrhagic disease Diseases 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A61K38/38—Albumins
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
- A61K38/385—Serum albumin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
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- C12Y304/21022—Coagulation factor IXa (3.4.21.22)
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- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21038—Coagulation factor XIIa (3.4.21.38)
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Abstract
The present invention relates to for treating or preventing the patient's bleeding with acquired coagulation factor deficiency disease, or the coagulation factor substitute products for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease.The product includes at least isolated factor (factor II) and isolated Antithrombin III (ATIII), and wherein the molar ratio between ATIII and factor II is at least 1:30.By applying the product, the risk of the thromboembolic complication of patient is reduced.
Description
Invention field
The present invention relates to for treating or preventing the patient's bleeding with acquired coagulation factor deficiency disease, or for treating
Or prevention has the coagulation factor substitute products of the patient's bleeding of coagulation factor congenital deficiency disease.
Background of invention
Relative to other treatment means, for example, the therapeutic plasma for promptly reversing vitamin K antagon, preferential recommendation
Prothrombin complex concentrate (PCC) (Tazarourte K et al. (EPAHK research) .Crit Care 2014;18(2):
R81).PCC Europe also used for many years, their license of Europe be not limited to vitamin K antagon reverse-they obtain extensively
General approval " treating and preventing the bleeding of the acquired deficiency of prothrombin complex coagulation factor ".PCC contain there are three types of or four kinds
Coagulation factor (factor II, IX and X, with or without factor Ⅴ II), and according to the difference of formula, the blood coagulation suppression comprising low dosage
Preparation such as protein C, protein s and heparin.
The mechanism of action of PCC is for understanding that their treatment use is important.Vitamin K antagon such as warfarin passes through
Reduce by four kinds of prothrombins, the level of VII, IX and X work, it is therefore an objective to prevent thromboembolism.For with threat to life
Bleeding patient, need these coagulation factors of quick-replaceable, and PCC serves as the concentrated source of required coagulation factor.?
Three factors and four factor PCC are explored to reverse for vitamin K antagon.However, due to lack factor Ⅴ II, it appears that three because
Sub- PCC is not as good as four factor PCC more suitable for patient (Dentali F et al. with international norm ratio (INR) > 3.7
Thromb Haemost 2014;112:621-23).
In wound and perioperative bleeding following, there are various coagulopathies in patient.PCC is solidifying by the key for ensuring enough levels
Blood factor-be especially factor II (factor) Lai Zengjia fibrin ferment generation, wherein be converted to fibrin ferment by activation because
Sub- X and the factor Ⅴ of activation are promoted.The hemostasis of wound and peri-operation period may be effectively facilitated with PCC treatment.Also table on evidence
It is bright to reverse direct FIIa or FXa inhibitor (DOAC) in the intracorporal blood coagulation resisting function of people using PCC.
For the anticoagulant therapy of DOAC induction, PCC cannot function as specific reversal agent.On the contrary, they improve vitamin K
The level of dependence coagulation factor.
Work as wound, when using PCC during perioperative bleeding following, the potential risk needs of thromboembolic complication are taken with caution
Method.In these environment-reverse the level of difference-Coagulative inhibitors agent and Procoagulants would generally with vitamin K antagon
It reduces.Target is to enhance the generation and/or fibrinous formation of fibrin ferment, promotes the grumeleuse of bleeding part to be formed, but cannot
Whole body forms grumeleuse in the entire circulatory system.According to the difference of formula, PCC contains the Coagulative inhibitors agent of low dosage, such as egg
White matter C, protein s and heparin.However, this does not eliminate risk (Grottke O et al. Blood of thromboembolic complication
2011;118:1943-51;Levy JH et al. Anesthesiology 2008;109:918-26;Mitterlechner T etc.
People J Thromb Haemost2011;9:729-37;Hanker Dusel C et al. Blood Coagul Fibrinolysis
2004;15:405-11;Rodgers GM.Am J Hematol 2012;87:898-902;Dickneite G et al. Anesth
Analg 2008;106:1070-7;Dickneite G, Pragst I.Br J Anaesth 2009;102:345-54;
Kaspereit F et al. Br J Anaesth 2010;105:576-82).
Many preclinical studies have studied application of the PCC in the treatments for bleeding caused by wound.All equal tables of research
Bright PCC can effectively restore to stop blooding, but also evidence suggests PCC can cause to promote blood coagulation effect, such as the thromboembolism in animal model
Complication and disseminated intravascular coagulation (DIC), therefore the ratio between risk and benefit (Grottke O et al. Blood should be considered always
2011;118:1943-51).
In clinical practice and zooscopy several years ago, PCC (Levy related to possible thromboembolic complication risk
JH et al. Anesthesiology 2008;109:918-26;Mitterlechner T et al. J Thromb Haemost
2011;9:729-37;Hanker Dusel C et al. Blood Coagul Fibrinolysis 2004;15:405-11).?
Later period the 1990s eliminates activation factor from most of PCC, it is therefore intended that improves safety.Factor II (fibrin ferment
It is former) be confirmed as the key determinant of current PCC thrombosis, it is therefore proposed that should according to factor II rather than factors IX
(Hanker Dusel C et al. Blood Coagul Fibrinolysis 2004 is marked in content;15:405-11).Circulation
Horizontal anticoagulant may also influence the thromboembolic complication risk of patient.PCC is described as balancing in the literature sometimes
(Kaspereit F et al. Br J Anaesth 2010;105:576-82;Josic D et al. Thromb Res 2000;
100:433-41;Ostermann H et al. Thromb Haemost 2007;98:790-7;Pabinger I et al. J Thromb
Haemost 2008;6:622-31;Riess HB et al. Thromb Res 2007;121:9-16;Wiedermann CJ,
Stockner I.Thromb Res2008;122 supplementary issue 2:S13-8).It is important to clarify, although these products may be solidifying
It is balance in terms of the ratio of blood factor II, VII, IX and X, but they are uneven in terms of the level of Procoagulants and inhibitor
Weighing apparatus.PCC is that efficient fibrin ferment generates drug: in trauma patient studies have shown that they cause intrinsic coagulation enzyme potential
It dramatically increases 3-4 days, this time limit is consistent with the 60-72 of factor II half-life period hour.
Pharmacovigilance must remember statistics indicate that may be very low using the risk of the thromboembolic complication of PCC, these
The main source of data is that vitamin K antagon reverses.
It has been proposed that should only apply the PCC of low dosage, and dose titration is carried out using diagnostic method as needed
(Honickel M et al. Thromb Haemost 2011;106:724-33).It (is wrapped in PCC furthermore it is possible to measure antithrombase
The most effective inhibitor of the activated form of the four kinds of coagulation factors contained) level, but, currently without evidence support about threshold value
How level disposes the preferred forms for having defective patient.Finally, for considereding to be in thromboembolic complication
The patient (such as the patient for having thromboembolic events history) of risk, monitoring may be suitable closely.With established urgent dimension
Raw element K antagonist reverses practice to compare, and it is significantly different using the method for PCC to consider that above-mentioned steps will lead to caution.
To especially when using anticoagulant therapy, in big bleeding or in the case where need emergency operation, provide in patients
Effectively there are medical needs for the safely effectively coagulant object of hemostasis control and bleeding prevention.
In addition, being deposited to the safely effectively coagulant object for providing quick-acting haemostatic powder control in perioperative bleeding following
In medical need.
Corresponding intervention should provide maximum interests superior portfolio, that is, provide maximum rush anthemorrhagic performance, cause simultaneously
The smallest potential thrombotic.
Summary of the invention
The first purpose of the invention is to provide a kind of improved coagulation factor substitute products, with patient described in the application
The reduction risk of thromboembolic complication is related after product, that is, has improved security feature.
According to second purpose, the treatment will be so that be able to carry out effective hemostasis control and bleeding is pre- in patients
It is anti-, i.e., other than improved security feature, even also have effects that enough effects improve.
According to third purpose, the applications of the safely effectively coagulation factor substitute products will be special so that in patient
Be not when using anticoagulant therapy, big bleeding or need emergency operation in the case where be capable of providing effective hemostasis control and
Bleeding prevention.
According to another purpose, the application of the safely effectively coagulation factor substitute products will be so that in peri-operation period
Quick-acting haemostatic powder control is capable of providing under bleeding.
According to another purpose, the application of the safely effectively coagulation factor substitute products will allow for maximum benefit
Beneficial superior portfolio provides maximum rush anthemorrhagic performance, while causing the smallest potential thrombotic.
Surprisingly, it was found that including at least factor (factor II) and Antithrombin III to patient's application
(ATIII) coagulation factor substitute products are administered in combination together with Antithrombin III and include at least factor (factor II)
Even coagulation factor substitute products minimize the thrombosis potentiality for inhibiting coagulation factor substitute products, while remaining enough
Even the effect of effect improves, as long as the molar ratio between ATIII and factor II is at least 1:30.Therefore, reduce patient's
Thromboembolic complication risk.Preferably, prevent pro-thrombotic from acting on.
The present invention further proves, can be prevented according to the molar ratio between the ATIII of another aspect and factor II
Excess thrombin, which generates, is higher than normal/physiological level.
In the first aspect, the present invention relates to coagulation factor substitute products, the products
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease;
The product includes at least isolated factor (factor II) and isolated Antithrombin III (ATIII), wherein
Molar ratio between ATIII and factor II is at least 1:30;And
The wherein product described by application, reduces the thromboembolic complication risk of patient.
In the second aspect, the present invention relates to prothrombin complex concentrates (PCC) and Antithrombin III (ATIII)
Combination, the combination
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease,
The PCC includes at least factor (factor II), factors IX, factor X and optional Coverage factor VII;And
The wherein combination described by application, reduces the thromboembolic complication risk of patient.
In the third aspect, the present invention relates to combination treatment, it includes application prothrombin complex concentrate (PCC) and
It is administered in combination Antithrombin III (ATIII),
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease,
The PCC includes at least factor (factor II), factors IX, factor X and optional Coverage factor VII;And
The wherein combination described by application, reduces the thromboembolic complication risk of patient.
According to the 4th aspect, the present invention relates to the drug coagulation factors for purposes disclosed herein to substitute suit
Product, the complete product include antithrombase including at least the first chamber of factor (factor II) and (ii) comprising (i)
The second chamber of III (ATIII), wherein the first chamber and the second chamber are provided in complete product, with
(a) is allowed to prepare mixture before administration, it has the molar ratio between at least ATIII of 1:30 and factor II, and/or
(b) mixture or composition is administered in combination, condition is that the molar ratio between the ATIII of application and the factor II of application is extremely
Few 1:30, wherein the composition described by application, reduces the thromboembolic complication risk of patient.
The 5th aspect, the present invention relates to the drug products comprising Antithrombin III (ATIII), be used for comprising
The product of factor (factor II) is administered in combination,
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease;
The factor (factor II) at least ATIII of 1:30 and factor II molar ratio and anticoagulant is wherein administered in combination
Hemase III (ATIII);
And the thromboembolic complication risk of patient is wherein reduced by product described in application.
According to another aspect, the present invention relates to the drug products comprising factor (factor II), it is used for and comprising anti-
The product of fibrin ferment III (ATIII) is administered in combination,
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease;
The factor (factor II) at least ATIII of 1:30 and factor II molar ratio and anticoagulant is wherein administered in combination
Hemase III (ATIII);
And the thromboembolic complication risk of patient is wherein reduced by product described in application.
The present invention relates to the coagulation factor of the purposes for any one of the claims substitutions to produce according to another aspect,
Product, wherein the product is any one prothrombin complex concentrate (PCC) of following two type:
3 factor coniplexes of Coverage factor II, IX and X, or
Additionally comprise 4 factor coniplexes of factor Ⅴ II;
The product includes Antithrombin III (ATIII), and wherein the molar ratio between ATIII and factor II is lower than 1:30,
Even being free of ATIII;
PCC is provided to be used to be administered in combination with the product comprising ATIII,
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease;
Wherein when be administered in combination when, be administered in combination ATIII specific factor II molar ratio be at least 1:30 factor II with
ATIII;
And the thromboembolic complication risk of patient wherein is reduced by the way that the PCC product and ATIII is administered in combination.
On the other hand, the present invention relates to coagulation factor substitute products;The product include at least isolated factor (because
Sub- II) and isolated Antithrombin III (ATIII), wherein the molar ratio between ATIII and factor II is at least 1:30.It is described
Product preferably have according to any one or more aspects disclosed herein or such as any one disclosed herein or
The composition of multiple embodiments.
The present invention relates to coagulation factor substitute products such as disclosed herein according to another aspect, is used in preparation such as this
Purposes in the medicament for the treatment of disclosed in application.
The present invention relates to method, this method according to another aspect,
(i) treat or prevent have acquired coagulation factor deficiency disease patient bleeding or
(ii) bleeding for the patient that there is congenital factor to lack is treated or prevented;
This method is carried out by applying coagulation factor substitute products to the patient,
The product includes at least isolated factor (factor II) and isolated Antithrombin III (ATIII), wherein
Molar ratio between ATIII and factor II is at least 1:30;
And the thromboembolic complication risk of patient is wherein reduced by product described in application.
Therefore, other in particular to following embodiments [1] to [48] or combinations thereof of the present invention:
[1] coagulation factor substitute products, the product
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease;
The product includes at least isolated factor (factor II) and isolated Antithrombin III (ATIII), wherein
Molar ratio between ATIII and factor II is at least 1:30;
And the thromboembolic complication risk of patient is wherein reduced by product described in application.
[2] the coagulation factor substitute products of the purposes according to embodiment [1] are used for, wherein the production described by application
Product reduce the thromboembolic complication risk of patient, in addition to product used in the reference therapy compared with reference therapy
ATIII and factor II between molar ratio lower than other than 1:30, the reference therapy is identical as the treatment.
[3] for the coagulation factor substitute products according to embodiment [1] or the purposes of embodiment [2], the wherein production
Product also include at least one of the isolated coagulation factor selected from factors IX, factor X and factor Ⅴ II.
[4] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein with after placebo treatment
Or the blood loss that do not treat is compared, and is reduced with the blood loss of patient after product treatment, wherein blood loss is preferably decreased to low
Blood loss in placebo treatment or after not treating 75%, lower than 70%, lower than 60%, lower than 55%, lower than 50%, be lower than
45%, lower than 40% or lower than 35%.
[5] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein compared with reference therapy,
The blood loss of patient is essentially identical after being treated with the product or only appropriateness increases, alternatively, wherein compared with reference therapy, with the production
The blood loss of patient is reduced after product treatment, it is preferable that compared with reference therapy, is reduced with the blood loss of patient after product treatment
At least 5%, at least 10%, at least 15% or at least 20%, wherein in addition to product used in the reference therapy ATIII with
For molar ratio between factor II lower than other than 1:30, the reference therapy is identical as the treatment,.
[6] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the mistake with reference therapy
Blood volume is compared, and is only moderately increased with the blood loss of patient after product treatment, and the appropriateness, which increases to amount to, is no more than 60%, no
More than 50%, it is no more than 40%, is no more than 30%, is no more than 20%, is no more than 15%, being no more than 10% or be no more than 5%,
In the product used in the reference therapy ATIII and factor II between molar ratio lower than other than 1:30, it is described
Reference therapy is identical as the treatment.
[7] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein with after placebo treatment
Or the time value for reaching hemostasis that do not treat is compared, and is reduced with the time value for reaching hemostasis of patient after product treatment,
In compared with the value after placebo treatment or the value that do not treat, it is described with the product treatment after reach hemostasis time value it is preferred
It is reduced at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% or at least 60%.
[8] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein compared with reference therapy,
With the product treatment after patient the time value for reaching hemostasis it is substantially the same or only appropriateness increase, or in which with reference therapy phase
Than being reduced with the time value for reaching hemostasis after product treatment, it is preferable that compared with the value after reference therapy, with the product
The time value for reaching hemostasis after treating is reduced at least 5%, at least 10%, at least 15% or at least 20%, wherein in addition to described
Molar ratio between the ATIII and factor II of product used in reference therapy lower than other than 1:30, the reference therapy with
The treatment is identical.
[9] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein compared with reference therapy,
Only moderately increased with the time value for reaching hemostasis of patient after product treatment, the appropriateness increase amount to be no more than 80%,
No more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20% or be no more than
10%, wherein molar ratio between the ATIII and factor II of the product used in the reference therapy is lower than other than 1:30,
The reference therapy is identical as the treatment.
[10] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the patient with
Prothrombin time (PT) value and/or activated partial factor I time (aPTT) value and reference after product treatment
The prothrombin time (PT) and/or activated partial factor I time (aPTT) value for the treatment of are compared to reduction at least 1.5
Times, at least 2.0 times, at least 2.5 times, at least 3.0 times, at least 3.5, at least 4.0, at least 4.5, at least 5.0, at least 7 times or extremely
It is 10 times (especially applying after the product about 1, about 2, about 3 and/or about 4 hours) few, wherein in addition to making in the reference therapy
Molar ratio between the ATIII and factor II of product is lower than other than 1:30, the reference therapy and the treatment phase
Together.
[11] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the patient with
The product treatment after prothrombin time (PT) value and/or activated partial factor I time (aPTT) value with peace
Console analog value and/or the activated partial factor I time of the prothrombin time (PT) treated after agent is treated or not
(aPTT) analog value is substantially the same when comparing and/or maximum deviation with described value, and condition is the maximum deviation
No more than 5.0,4.0,3.0,2.5,2.0 or 1.5 times, especially about 1 hour after applying the product, about 2 hours, about 3 is small
When and/or administration after about 4 hours when.
[12] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein solidifying with reference therapy
Hemase generates, and the value that especially fibrin ferment generates potentiality (ETP) is compared, and is generated with the fibrin ferment of patient after product treatment
Value, especially fibrin ferment generate potentiality (ETP) value reduce at least 5%, at least 10%, at least 15%, at least 20%, at least
25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50%, especially 1 hour after applying the product,
At 2 hours and/or 3 hours, wherein in addition to mole between the ATIII and factor II of the product used in the reference therapy
Than lower than other than 1:30, the reference therapy is identical as the treatment.
[13] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the D- with reference therapy
The value of dimerization bulk concentration (DD) is compared, and the value of the d-dimer concentration (DD) of patient's blood reduces at least after with product treatment
1.5, at least 2, at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, until
Few 7, at least 8, at least 9, or at least 10 times, about 1 hour, about 2 hours, about 3 hours and/or about especially after applying the product
At 4 hours, wherein in addition to the molar ratio between the ATIII and factor II of the product used in the reference therapy is lower than 1:30
In addition, the reference therapy is identical as the treatment.
[14] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the product also includes point
From Coagulative inhibitors agent at least one, be selected from protein s, protein C and protein Z.
[15] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the product also includes liver
Element.
[16] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the product also includes white
Albumen.
[17] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein factor II is unactivated
, and if there is in coagulation factor substitute products, coagulation factors factor IX, factor X and factor Ⅴ II independently are not living
Changing or activation, preferably all the factor is non-activated.
[18] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the product pass through it is quiet
Patient is applied in arteries and veins, in part or bone.When intravenous provide, by intravenous infusion or intravenous push agent can be passed through
Amount applies the product.
[19] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein provide in the product
The activity level of factor II is between 10-80IU/mL, between 15-60IU/mL, preferably between 20-48IU/mL.
[20] the coagulation factor substitute products of the purposes according to any one of embodiment are used for, wherein if there is in blood coagulation
In factor substitute products, then coagulation factors factor IX, factor X and the factor are independently provided in the product with following activity level
VII:
Factors IX is between 10-50IU/mL, between 15-40IU/mL, preferably 20-31IU/mL,
Factor X is between 10-100IU/mL, in 15-80IU/mL times, preferably 22-60IU/mL, and
Factor Ⅴ II is between 5-50IU/mL, between 5-40IU/mL, preferably 10-25IU/mL.
[21] the coagulation factor substitute products of the purposes according to any one of embodiment are used for, wherein if there is in blood coagulation
In factor substitute products, then inhibitor protein matter S, protein C and egg are independently provided in the product with following activity level
White matter Z:
Protein s are between 5-50IU/mL, between 10-45IU/mL, preferably 12-38IU/mL,
Protein C is between 10-60IU/mL, between 10-50IU/mL, preferably 15-45IU/mL, and
Protein Z is between 5-60IU/mL, between 5-50IU/mL, preferably 10-45IU/mL.
[22] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the substitute products applied
Active dose in about 5IU/kg between about 100IU/kg, in about 10IU/kg between about 75IU/kg or in about 10IU/kg
To between about 50IU/kg, condition is the activity that activity refers to factor II or factors IX (if present).
[23] the coagulation factor substitute products of the purposes according to any one of embodiment [3] to [22], wherein blood coagulation are used for
Factor II and the activity level of factors IX are in equilibrium ratio, and condition is one of two kinds of factors and another activity level in product
Difference is no more than 3,2.5,2.0,1.5 or 1.2 times.
[24] the coagulation factor substitute products of the purposes of any one of the embodiment above are used for, wherein ATIII and factor II
Between molar ratio be not higher than 1:0.5.
[25] the coagulation factor substitute products of the purposes of any one of the embodiment above are used for, wherein ATIII and factor II
Between molar ratio between 1:30 to 1:0.5, preferably in 1:28 between 1:0.5,1:25 to 1:0.5 it
Between, in 1:24 between 1:0.5, in 1:23 between 1:0.5, in 1:22 between 1:0.5, in 1:21 between 1:0.5,
1:20 is between 1:0.5, in 1:18 between 1:0.5, in 1:15 between 1:0.5, in 1:12 between 1:0.5 or in 1:10
To 1:0.5.
[26] the coagulation factor substitute products of the purposes of any one of the embodiment above are used for, wherein ATIII and factor II
Between molar ratio between 1:30 to 1:1, preferably in 1:28 between 1:1, in 1:25 between 1:1,1:
24 between 1:1, in 1:23 between 1:1, in 1:22 between 1:1, and in 1:21 between 1:1, in 1:20 between 1:1,
In 1:18 between 1:1, in 1:15 between 1:1, in 1:12 between 1:1 or between 1:10 to 1:1.
[27] the coagulation factor substitute products of the purposes of any one of the embodiment above are used for, wherein ATIII and factor II
Between molar ratio 1:30 to 1:2 between, preferably in 1:28 between 1:2, in 1:25 between 1:2, in 1:24
To between 1:2, in 1:23 between 1:2, in 1:22 between 1:2, in 1:21 between 1:2, in 1:20 between 1:2,
1:18 is between 1:2, in 1:15 between 1:2, in 1:12 between 1:2 or between 1:10 to 1:2.
[28] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein ATIII is that blood plasma spreads out
Raw protein or recombinant protein.
[29] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein factor II and/or another
Outer at least one (if present) selected from factors IX, the coagulation factor of factor X and factor Ⅴ II is that recombinant protein or blood plasma are derivative
Protein.
[30] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein ammonia first ring is administered in combination
Sour (TXA), preferable amount is between 10 to 20 mg/kg weight.
[31] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the treatment or pre-
Bleeding in the anti-acquired deficiency disease comprising treatment and peri-operation period prevention prothrombin complex coagulation factor, especially by
Bleeding in deficiency disease caused by treating under vitamin K antagon or the excessive situation of vitamin K antagon needs fast at this time
Speed corrects deficiency disease;Alternatively, wherein the treatment or prevention include that treatment and peri-operation period prevent any vitamin k-dependent
Bleeding in the congenital deficiency disease of coagulation factor, especially the specific coagulation Factor products of purifying not using when.
[32] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the patient suffers from
Any kind of wound correlation coagulopathy, including the relevant coagulopathy of perioperative bleeding following.
[33] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the patient suffers from
Severe haemorrhage and there is vitamin K-dependent clotting factor to lack, especially there is acquired blood coagulation disorders, such as liver disease
Disease etc., or there is hemophilia B, especially with inhibitor.
[34] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the patient is previous
Oral anticoagulant (the DOAC/ for having used vitamin K antagon, especially oral vitamin K antagonist or directly having worked
NOAC it) treats, preferably direct FIIa or FXa inhibitor, and needs quickly to reverse vitamin K antagon or DOAC/NOAC
Blood coagulation resisting function.
[35] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the patient with
With at least one situation of following coagulopathy compared with health volunteer before the product treatment:
Prothrombin time (PT) more than 1.5 times extends,
The former time (aPTT) of activated partial thrombokinase more than 1.5 times extends,
Whole blood clotting time (WBCT) more than 1.5 times extends,
Rotational thromboelastography parameter EXTEM-CT or EXTEM-CFT and FIBTEM-MCF is reduced, or
The coagulation factor of prothrombin complex is lacked or is substantially reduced.
[36] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein in addition to the production
Except product treatment, patient is also treated at least one of following option in advance, subsequently or simultaneously:
Applied volume swelling agent or resuscitation fluid, especially application ringer lactate, salt water and/or hydroxyethyl starch
(HES/HAES),
It applies packed red cells (PRBC),
It applies fresh frozen plasma (FFP),
Blood platelet is applied, or
Apply fresh whole blood.
[37] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein in addition to the production
Except product treatment, patient uses substitute products (such as cold hypostasis) also in advance, subsequently or simultaneously or fibrinogen concentrate is together
Treated, preferably in 5 mg/kgs between 150 mg/kg weight, in 10 mg/kgs to 100 mg/kgs
Between, in 20 mg/kgs between 80 mg/kg weight, preferably 25 mg/kgs to 60 mg/kg weight it
Between fibrin commercial weight application substitute products or fibrinogen concentrate in range.
[38] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the product is used as one
Line single substance treatment, be preferred for after treating significant bleeding, especially peri-operation period or wound, preferably with the K that is deficient in vitamin
Dependence coagulation factor is related, and further preferably external vitamin K is anticoagulant.
[39] the coagulation factor substitute products for the purposes of any one of the embodiment above, wherein the patient is controlling
There is Injure severity score (ISS) > 16 and/or serious shock before treating.
[40] the coagulation factor substitute products of the purposes according to any one of embodiment [3]-[39] are used for, wherein the product
It is the prothrombin complex concentrate (PCC) of one of the following two kinds type:
3 factor coniplexes of Coverage factor II, IX and X;Or
Additionally comprise 4 factor coniplexes of factor Ⅴ II;
The product also includes Antithrombin III (ATIII), and wherein the molar ratio between ATIII and factor II is at least
1:30.In general, prothrombin complex concentrate (PCC) according to the present invention is also referred to as improved in this application
PCC, to emphasize the raised ATIII content compared with PCC well known in the prior art.
[41] the coagulation factor substitute products of the purposes of any one of the embodiment above are used for, wherein thromboembolic complication
Risk reduction show as artery or venous thronbosis, the mitigation of myocardial infarction and/or disseminated intravascular coagulation (DIC).
[42] combination of prothrombin complex concentrate (PCC) and Antithrombin III (ATIII), the combination
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease,
PCC includes at least factor (factor II), factors IX, factor X and optional Coverage factor VII, and condition is application
ATIII and factor II molar ratio be at least 1:30;And
Wherein by applying the combination, the thromboembolic complication risk of patient is reduced.
[43] combination treatment, it includes application prothrombin complex concentrate (PCC) and combined administration Antithrombin III
(ATIII), the therapy
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease,
PCC includes at least factor (factor II), factors IX, factor X and optional Coverage factor VII, and condition is application
ATIII and factor II molar ratio be at least 1:30;And
Wherein by applying the combination, the thromboembolic complication risk of patient is reduced.
[44] the drug coagulation factor for the purposes according to any one of embodiment [1]-[41] substitutes complete product, institute
It includes Antithrombin III including at least the first chamber of factor (factor II) and (ii) that complete product, which is stated, comprising (i)
(ATIII) second chamber, wherein the first chamber and the second chamber provide in complete product, to allow
(a) mixture is prepared before administration, and the molar ratio between the ATIII that it has and factor II is at least 1:30 and/or (b) is used for
The mixture or composition is administered in combination, condition is that the molar ratio between the ATIII of application and the factor II of application is at least
1:30, wherein reducing the thromboembolic complication risk of patient by applying said compositions.
[45] drug products, it includes Antithrombin III (ATIII), is joined with the product comprising factor (factor II)
Close application, the product
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease;
Factor (factor II) and Antithrombin III (ATIII), the ATIII having and the factor is wherein administered in combination
Molar ratio between II is at least 1:30;
And the thromboembolic complication risk of patient wherein is reduced by the way that the product is administered in combination.
[46] drug products, it includes the factor being administered in combination with the product comprising Antithrombin III (ATIII)
(factor II), the product
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease;
Factor (factor II) and Antithrombin III (ATIII), the ATIII having and the factor is wherein administered in combination
Molar ratio between II is at least 1:30;
And the thromboembolic complication risk of patient wherein is reduced by the way that the product is administered in combination.
[47] the coagulation factor substitute products of the purposes according to any one of embodiment [1]-[41] are used for, wherein the product
For the prothrombin complex concentrate (PCC) of one of the following two kinds type:
3 factor coniplexes of Coverage factor II, IX and X, or
Additionally comprise 4 factor coniplexes of factor Ⅴ II;
The product includes Antithrombin III (ATIII), and wherein the molar ratio between ATIII and factor II is lower than 1:30
Even being free of ATIII;
PCC is provided to be used to be administered in combination with the product comprising ATIII,
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease;
Wherein when solid is applied, be administered in combination have factor II that ATIII and factor II molar ratio are at least 1:30 and
ATIII;
Wherein by the way that the PCC product is administered in combination together with ATIII, the thromboembolic complication wind of patient is reduced
Danger.
[48] a kind of method, this method are used for
(i) patient's bleeding with acquired coagulation factor deficiency disease is treated or prevented, or
(ii) patient's bleeding that there is congenital factor to lack is treated or prevented;
It is carried out by applying coagulation factor substitute products to the patient,
The product includes at least isolated factor (factor II) and isolated Antithrombin III (ATIII), wherein
Molar ratio between ATIII and factor II is at least 1:30;
And the thromboembolic complication risk of patient wherein is reduced by the way that the product is administered in combination.
The embodiment above [1] to [48] can be with times of the feature of other embodiments or aspect disclosed herein
It anticipates one or more combinations.
Brief Description Of Drawings
Fig. 1 shows the search procedure that hemodilution, processing, experimental injury of kidney and haemostatic effect are assessed.Abbreviation: HES, hydroxyl
Hydroxyethyl starch;PCC (prothrombin complex concentrate), ATIII (Antithrombin III);
After Fig. 2 shows the combined treatment with salt water (placebo), PCC, ATIII or PCC and ATIII, in hemodilution
Total blood loss after rabbit Plays injury of kidney.The data of display represent the median with range.Abbreviation: PCC (fibrin ferment
Former compound concentrate);
After Fig. 3 is shown in the combined treatment with salt water (placebo), PCC, ATIII or PCC and ATIII, in hemodilution
Rabbit Plays injury of kidney after reach time of hemostasis.The data of display represent median.Abbreviation: (factor is multiple by PCC
Close object concentrate), ATIII (Antithrombin III);
Fig. 4 a is shown in rabbit medium sized vein in the presence of the combined treatment with salt water (placebo), PCC or PCC and ATIII
Thrombus scoring after thrombosis.The data of display represent median.Abbreviation: PCC (prothrombin complex concentrate),
ATIII (Antithrombin III);
Fig. 4 b is shown in rabbit medium sized vein in the presence of the combined treatment with salt water (placebo), PCC or PCC and ATIII
Wet weight of thrombus after thrombosis.The data of display represent median.Abbreviation: PCC (prothrombin complex concentrate),
ATIII (Antithrombin III);
Fig. 5 shows the total blood loss after second of hepatic injury of pig.Compared with control group and monotherapy PCC50 treatment group,
The combination of PCC and ATIII reduces blood loss;
Fig. 6 shows the pig data of the survival indicated with Kaplan-Meier curve;
Fig. 7 shows pig data (MPAP, (average value ± standard deviation) of average lung pressure;
Fig. 8 shows the antithrombase concentration (average value ± standard deviation) after pig wound and haemorrhagic shock;
Fig. 9 shows the fibrinogen concentration (average value ± standard deviation) after pig wound and haemorrhagic shock;
With the d-dimer (average value ± standard deviation) of changing course after Figure 10 display pig wound and haemorrhagic shock;
(average value ± standard deviation) is generated with the fibrin ferment of changing course after Figure 11 display pig wound and haemorrhagic shock;
With prothrombin time (PT) (average value ± standard of changing course after Figure 12 display pig wound and haemorrhagic shock
Deviation);And
Figure 13 (is put down after showing pig wound and haemorrhagic shock with the activated partial thrombokinase time (aPTT) of changing course
Mean value ± standard deviation).
Definition
Unless otherwise defined, otherwise all technical and scientific terms used herein have and fields of the present invention
The identical meaning of the normally understood meaning of those of ordinary skill.Although with those similar or equivalent timess described in this application
Where method and material implementation for use in the present invention or test, but describe preferred method and material.For mesh of the invention
, following term is defined as follows.
The article " one " used herein and "one" one or more than one (i.e. at least one) language to refer to the article
Method object.As example, " element " indicates an element or more than one element.
So-called " about " amount of referring to, horizontal, numerical value, quantity, frequency, percentage, size, size, dosage, weight or length with
Reference variable, horizontal, numerical value, quantity, frequency, percentage, size, size, dosage, weight, length or described herein its
He compares variation up to 30,25,20,15,10,9,8,7,6,5,4,3,2 or 1% at unit.
" Antithrombin III (ATIII) " of the invention is functional plasma protease inhibitors ATIII, is especially separated
, that is, the functional ATIII purified.ATIII is preferably people ATIII.
" coagulation factor " of the invention is functional factor, is especially separated, that is, the functional blood coagulation purified because
Son.Coagulation factor is preferably human blood coagulation.
In this application, unless the context otherwise requires, otherwise word " comprising ", "comprising" and " containing " will be understood as
Imply to include the step or element or step or element group, but is not excluded for any other step or element or step or element
Group.
So-called " consist of " mean include and be limited to phrase " by ... form " after any content.Therefore,
The element that phrase " consist of " indicates listed is required or enforceable, and other element is not present.So-called " base
In sheet by ... form " refer to any element including listing after the phrase, and be limited to not interfere or facilitate this
The other element of the activity or behavior specified in open for listed elements.Therefore, phrase " substantially by ... form " table
Show that listed elements are required or enforceable, but other element is optional and may exist or be not present, this depends on
The activity or behavior of listed elements whether are substantially influenced in them.
" separation " in the sense of the present invention refer to corresponding coagulation factor or coagulation factor mixture or ATIII from
(derived from blood plasma) is purified in human plasma or is purified from culture medium if recombination is generated.Purifying, which refers to, in the sense of the present invention appoints
The purifying of what type, compared with from the solution of mixture or ATIII for initially obtaining corresponding coagulation factor or coagulation factor,
It leads to the more high bioactivity of the mixture of the coagulation factor or coagulation factor or ATIII/ milligrams of total protein contents, or
Reach the coagulation factor or blood coagulation mixture or final administration in the more high bioactivity of the ATIII/ml liquid of patient.
Coagulation factor or the active international unit (" IU ") of ATIII are equivalent in 1 milliliter of human normal plasma and accordingly coagulate
The amount of blood factor or ATIII.
Coagulation factor substitute products of the invention can be provided, and be referred to as the prothrombin complex concentrate of modification
(PCC).The prothrombin complex concentrate (PCC) of modification in the sense of the present invention includes at least isolated coagulation factor FII,
FIX, FX (in the application be also referred to as 3 factor coniplexes) or isolated coagulation factor FII, FIX, FX and FVII are (in this application
Also referred to as 4 factor coniplexes) combination.It is according to the present invention to change compared with PCC well known in the prior art (i.e. routine PCC)
Into PCC also include at least Antithrombin III (ATIII), wherein the molar ratio between ATIII and factor II is at least 1:30.
The isolated coagulation factor FII, FIX, FX and FVII of improved PCC can be originated from human blood or such PCC can be from
The coagulation factor of recombinant expression reconstructs, wherein the antigen of the coagulation factor FVII, FIX, FX and FVII of the recombinant expression and work
Property the PCC of blood is originated from than being equivalent to, condition is in addition improved PCC includes at least Antithrombin III (ATIII), wherein
Molar ratio between ATIII and factor II is at least 1:30.
Coagulation factor substitute products of the invention include every kind of individual coagulation factor being present in liquid, or if
Freeze-drying storage in a liquid after reconstructing before injection.If not stated otherwise, the coagulation factor that product of the present invention provides
Concentration refers to the concentration of coagulation factor present in liquid, or such as fruit product stores, then is injecting especially in terms of IU/mL
It is lyophilized in a liquid after preceding reconstruct.
" patient " or " subject " for applying product of the present invention is animal or people, preferably people.In some aspects, people is paediatrics
Patient.In other respects, people is adult patients.
" substantially " or " main " means nearly completely or completely, for example, the 95% of certain specified rates, 96%, 97%,
98%, 99% or higher.
Detailed description of the invention
Coagulation factor
Functional factor II (FII) shows the bioactivity of factor, and factor represents fibrin ferment (FIIa)
Inactive proenzyme.After coagulation cascade activation, conversion of the factor to fibrin ferment occurs, the latter is a variety of in blood coagulation system
Activation function includes fibrinogen to fibrinous conversion, factor XIII (FXIII) activation for activation blood coagulation because
Sub- XIII (XIIIa), FV and FVIII activation are FVa and VIIIa, platelet activation etc. after thrombin receptor partial proteolytic.
The bioactivity of functional factor IX (FIX) display inactivation FIX, converts Viability in Activated Coagulation
FIXa.FIXa and its coenzyme F VIIIa forms compound and represents tenase compound, and inactivation FX is cracked into its active shape
Formula Fxa.
The bioactivity of functional factor X (FX) display inactivation FX, converts Viability FXa after Activated Coagulation.
FXa and its coenzyme F Va forms compound, represents prothrombinase complex, and inactive factor (FII) is cracked
Active enzyme thrombin (FIIa).
The bioactivity of functional factor FVII (FVII) display inactivation FVII, is converted to during Activated Coagulation
FVIIa.Inactivation FX is converted Viability FXa together with tissue factor by FVIIa.In addition, inactivation FIX can be converted to by FVIIa
Active FIXa.
Can according to L.Thomas:Clinical Laboratory Diagnostics, TH-Books, Frankfurt,
1998, the 17th chapter measures the activity of above-mentioned coagulation factor.
Coagulation factor use herein can derive from human plasma or serum or can recombinate to obtain.
Coagulation factor used in the present invention includes the protein of the amino acid sequence with native human Factor.Also wrap
Containing the coagulation factors with the amino acid sequence moderately modified, it may for example comprise the modification of -terminal amino acid missing or addition
The end N-, as long as these protein substantially retain the activity of coagulation factor.Coagulation factor in above-mentioned definition also includes
There may be and from an individuals to another ontogenetic Natural allelic version.Blood coagulation in above-mentioned definition
The factor also includes the variant of this kind of coagulation factor.This kind of variant and one or more amino acid residues from wild-type sequence are not
Together.The example of this species diversity may include truncating N- by one or more amino acid residues (such as 1 to 10 amino acid residue)
And/or the end C-, or one or more additional residues are added at N- and/or C, such as residual in the end N- addition methionine
Base and conserved amino acid replace, i.e., the substitution carried out in the amino acid group with similar features, for example, (1) small amino
Acid, (2) acidic amino acid, (3) polar amino acid, (4) basic amino acid, (5) hydrophobic amino acid, (6) aromatic amino acid.
The example of this kind of conservative substitution is as shown in the table.
As described above, functional factor used in the present invention is included in solution and/or shows on cell surface
The coagulation factor molecule of bioactivity.
Term " recombination " refers to, for example, coagulation factor or coagulation factor variant have passed through genetic engineering technology in host's life
It is generated in object.
Host cell of the invention can be used for generating in the method for human blood coagulation.This method includes:
A) host cell of the invention is cultivated under conditions of expressing one or more human blood coagulations;With
B) one or more human blood coagulations are optionally recycled from host cell or culture medium.
The degree and position of glycosylation or other posttranslational modifications can be according to selected host cell and host cells
The difference of the property of environment and change.When referring to specific amino acid sequence, the posttranslational modification of such sequence is included in this Shen
Please in.
It is needed with high level production recombinant protein by the cDNA of above-mentioned modification and recombination table in suitable host cell
Be assembled into effective transcriptional units together up to the suitable regulating element in carrier, can according to for those skilled in the art and
Say that known method is bred in various expression systems.Effective transcription regulatory element, which can be originated from, has zooblast as it
The virus of natural host or chromosomal DNA from zooblast.Preferably, can be used from simian virus 40, adenovirus,
The duplicate promoter-enhancer combination in the long end of BK polyomavirus, human cytomegalovirus or Rous sarcoma virus, is included in dynamic
The promoter-enhancer of strong composing type open gene in object cell combines, such as beta-actin or GRP78.In order to obtain from
The stable high-level mRNA of cDNA transcription, transcriptional units should contain encoding transcription termination-polyadenylic acid in its 3'- proximal part
Change the region of DNA of sequence.Preferably, the sequence is from simian virus 40 early transcription area, rabbit beta-globin gene or people's tissue
Type activator of plasminogen gene.
Then cDNA is integrated into the genome of suitable host cell line to express coagulation factor.Preferably, this is thin
Born of the same parents system should be the animal cell line of vertebrate origin, to ensure correctly to fold, the synthesis of Gla structural domain, and disulfide bond formation,
The glycosylation of asparagine connection, the glycosylation and other posttranslational modifications and secretion of O- connection enter culture medium.Other are turned over
The example modified after translating is the hydroxylating and proteolysis processing of nascent polypeptide chain.The example for the cell line that can be used is monkey
COS- cell, mouse L- cell, mouse C127- cell, hamster BHK-21 cell, human embryo kidney 293 cells and preferred hamster CHO-
Cell.Due to its complicated posttranslational modification, recombinant blood coagulation factor is preferably expressed in human cell line.
The recombinant expression carrier for encoding corresponding cDNA can be imported into animal cell line in several different ways.For example, can
To generate recombinant expression carrier from the carrier based on different animals virus.These example is to be based on baculoviral, vaccinia virus,
The carrier of adenovirus and preferred bovine papilloma virus.
The transcript unit for encoding corresponding DNA can also be imported into zooblast together with another recombination, the gene
The dominant selectable marker that can be used as in these cells works, and in order to separate specific cells clone, these clones will weigh
Group DNA is integrated into its genome.The example of such dominant selectable marker gene is to confer to Geneticin (G418)
Resistance Tn5 aminoglycoside phosphotransferase, assign the hygromix phosphotransferase to the resistance of hygromycin and assign to fast
The puromycin acetyltransferase of the resistance of purine mycin.The recombinant expression carrier for encoding this kind of selected marker can reside in and compile
It on the identical carrier of cDNA of the desired protein of code, or can be encoded on individual carrier, which is imported into simultaneously
And be integrated into the genome of host cell, frequently result in the close physical connection between different transcriptional units.
The other kinds of selectable marker gene that can be used together with the cDNA of desired protein is based on coding dihydro
The various transcriptional units of folic acid reductase (dhfr).Such channel genes are being lacked into the active cell of endogenous dhfr
Afterwards, preferred Chinese hamster ovary celI (DUKX-B11, DG-44) will be such that these genes grow in the culture medium for lacking nucleosides.This kind of culture
One example of base is the Ham's F12 of no hypoxanthine, thymidine and glycine.These dhfr genes can be with coagulation factor
CDNA transcriptional units are imported into together in the Chinese hamster ovary celI of the above-mentioned type, or are connected in same vehicle or on different carriers,
To generate the dhfr positive cell line for generating recombinant protein.
If above-mentioned cell line is grown in the presence of cytotoxicity dhfr inhibitor methotrexate (MTX), will appear to first ammonia
The resistant New cell line of pterin.Due to the amplification quantity of the transcriptional units of the dhfr and desired protein of connection, these
Cell line can generate recombinant protein with increased rate.When breeding these with the methotrexate (MTX) (1-10000nM) for increasing concentration
When cell line, the New cell line that desired protein is generated with very high rate can be obtained.
The above-mentioned cell line for generating desired protein can advise greatly in the culture that suspends or on various solid supports
Mould growth.The example of these carriers is microcarrier based on glucan or collagen matrices or doughnut or various ceramics
The solid support of material forms.In cell suspension culture or grown on microcarriers, the culture of above-mentioned cell line can be with
It is carried out as bath culture or as perfusion culture, and the continuous production conditioned medium within the extended period.Therefore, root
According to the present invention, above-mentioned cell line is very suitable for developing the industrial method for producing desired recombinant protein.
It can be by diversified biochemical method and chromatographic process, including the use of albumen desired in cell culture medium
Between matter and other substances size, charge, hydrophobicity, solubility, in terms of difference method, concentration
The recombinant protein accumulated in the culture medium of the secretory cell of the above-mentioned type with purifying.
One example of this purifying is that recombinant protein is adsorbed onto monoclonal antibody, which is fixed on solid
On body support.After desorption, protein can be further purified by various chromatographic techniques based on above-mentioned property.
It is preferred that purifying coagulation factor of the invention, either being generated by recombination method or being obtained from human plasma, reach
To >=60% purity, more preferably >=80% purity, particularly preferably pharmacy pure state, relative to pollution macromolecular, especially
It is other protein and nucleic acid, it is pure which is greater than 95%, and is free of pathogen and pyrogen.
Coagulation factor described in the present invention can be configured to the pharmaceutical preparation for therapeutical uses.It can be by the egg of purifying
White matter is dissolved in the aqueous buffer of conventional physiological compatible, optional drug excipient can be added thereto to obtain
Pharmaceutical preparation.
Such pharmaceutical carrier and excipient and suitable pharmaceutical preparation be it is well-known in the art (see, for example,
" Pharmaceutical Formulation Development of Peptides and Proteins ", Frokjaer etc.
People Taylor&Francis (2000) or " Handbook of Pharmaceutical Excipients ", the 3rd edition, Kibbe etc.
People Pharmaceutical Press (2000)).Particularly, the pharmaceutical composition comprising polypeptide variants of the present invention can be configured to
Freeze-drying or stable soluble form.Polypeptide variants can be lyophilized by a variety of methods known in the art.Lyophilized preparation is using
It is preceding to be reconstructed by the way that one or more pharmaceutically acceptable diluents such as sterile water for injection or sterile saline solution is added.
By any pharmaceutically suitable method of application by the formulation delivered of composition to individual.Various delivery systems are
Know, and can be used for applying the composition by any convenient way.It is preferred that the composition that systemic administration is of the invention.For
Whole body uses, and coagulation factor of the invention is formulated for parenteral (such as intravenously, subcutaneously, intramuscular, peritonaeum according to conventional methods
It is interior, intracerebral, intrapulmonary, intranasal or transdermal or vagina) or enteral (such as oral or rectal) delivering.Most preferred administration method is quiet
In arteries and veins and subcutaneous administration.Preparation can be by being transfused or injecting continuous administration.Some preparations cover slow-released system.
Coagulation factor of the invention is applied to patient with treatment effective dose, it is intended that be enough to generate the agent of desired effects
Amount, prevention or the seriousness or diffusion for mitigating treated illness or indication, it is intolerable bad without reaching generation
The dosage of side effect.Precise dosage depends on many factors, such as indication, preparation, method of application, it is necessary to each corresponding suitable
It answers in the preclinical and clinical test of disease and determines.
Antithrombin III (ATIII)
Functional Antithrombin III (ATIII) shows the bioactivity of plasma protein enzyme inhibitor Antithrombin III.People
It is about 58kDa, the glycoprotein containing 432 amino acid that ATIII, which is a kind of molecular weight,.Plasma protein enzyme inhibitor ATIII makes to coagulate
Hemase and the enzyme for being responsible for generating fibrin ferment inactivate.ATIII shows the sequence with serpin gene family member
Column, structure and function homology.Serpin inhibits its target enzyme by substrate inhibition mechanism of committing suiside.ATIII is special
It Yi Zhi not fibrin ferment, activation factor X (FXa) and activation factor IX (FIXa).
The egg of the amino acid sequence with natural human ATIII is preferably comprised for Antithrombin III (ATIII) of the invention
White matter.Also comprising the ATIII with the amino acid sequence moderately modified, it may for example comprise what -terminal amino acid was lacked or added
The end N- of modification, as long as these protein substantially retain the activity of ATIII.ATIII in above-mentioned definition also includes
There may be and from an individuals to another ontogenetic natural allelic variation.ATIII in above-mentioned definition is also
Variant including this ATIII.This kind of variant is different from one or more amino acid residues of wild-type sequence.It is provided above
The example of this species diversity of coagulation factor.As described above, functionality ATIII used in the present invention be included in solution in and/or
The ATIII molecule of bioactivity is shown on cell surface.Term " recombination " refers to, for example, ATIII or ATIII variant has led to
Genetic engineering technology as described above is crossed to generate in host organism.
Molar ratio
According to the present invention, factor (factor II) and Antithrombin III (ATIII) are used to treat the trouble for having this to need
Person, the molar ratio between the ATIII applied and the factor II applied are at least about 1:30.It therefore, particularly can be near
Molar ratio between the ATIII according to the present invention and factor II of few about 1:30 is interpreted as the lower limit of ATIII.
Product of the invention include at least factor (factor II) and Antithrombin III (ATIII), wherein ATIII and
Molar ratio between factor II is at least 1:30.It is not intended to by any theoretical constraint, it is believed that described relative to factor
Minimum mole of ATIII level is ensured in particular in prothrombin activation, be can use enough ATIII molecules and is combined excessively
Fibrin ferment or factor Xa, to limit, excessive fibrin ferment is generated and/or fibrin is formed, and thus by thromboembolism
Situation, that is, thromboembolic complication risk is reduced to bottom line or inhibits them.Therefore, the ATIII level ensures then
Product Therapeutic safety improvement.Mole between another preferred embodiment ATIII and factor II according to the present invention
Than being at least 1:29, at least 1:28, at least 1:27, at least 1:26, at least 1:25, at least 1:24, at least 1:23, at least 1:22,
At least 1:21, at least 1:20, at least 1:19, at least 1:18, at least 1:17, at least 1:16 at least 1:15, at least 1:14, at least 1:
13, at least 1:12, at least 1:11, even at least 1:10.
Molar ratio no more than about 1:0.5 according to preferred embodiment, between ATIII and factor II.It is not intended to by any
Theoretical constraint, it is believed that ATIII especially ensures horizontally relative to this mole of upper limit of factor in prothrombin activation,
Still there are enough free fibrin ferments to can be used for catalysis fibre albumen as far as fibrinous reaction.Therefore, the ATIII is horizontal really
It protects enough fibrin ferments to generate, fibrin forms and therefore provides enough effects.According to further preferred embodiment,
Molar ratio no more than about 1:1 between ATIII and factor II.According to further preferred embodiment, ATIII and factor II it
Between molar ratio no more than about 1:2.
The lower limit of any ATIII can be combined with the upper limit of any ATIII.
Molar ratio between ATIII and factor II it is further preferred between 1:30 to 1:0.5, preferably exist
In the range of 1:10 to 1:0.5.Molar ratio between ATIII and factor II is excellent further preferably in the range of 1:30 to 1:1
It is selected in the range of 1:10 to 1:1.According to another preferred embodiment, the molar ratio between ATIII and factor II is 1:
In the range of 10 to 1:2.
Any molar ratio according to the present invention refers to the ratio between the molar concentration of corresponding protein.
Molar ratio in the sense of the present invention be by apply before applied protein molar concentration (especially blood coagulation because
In sub- substitute products) formed.Since patient has had the one or more wait apply of certain endogenous levels under certain conditions
Protein, therefore the molar ratio generated in vivo may be different from the molar ratio of protein of the invention.
Molar ratio between ATIII and factor II is further preferably in 1:30 between 1:0.5, preferably in 1:28 to 1:
Between 0.5, in 1:25 between 1:0.5, in 1:24 between 1:0.5, in 1:23 between 1:0.5,1:22 to 1:0.5 it
Between, in 1:21 between 1:0.5, in 1:20 between 1:0.5, in 1:18 between 1:0.5, in 1:15 between 1:0.5,
1:12 is between 1:0.5, or between 1:10 to 1:0.5.
Molar ratio between ATIII and factor II further preferably in 1:30 between 1:1, preferably 1:28 to 1:1 it
Between, in 1:25 between 1:1, in 1:24 between 1:1, in 1:23 between 1:1, in 1:22 between 1:1, in 1:21 to 1:
Between 1, in 1:20 between 1:1, in 1:18 between 1:1, in 1:15 between 1:1, in 1:12 between 1:1, or 1:
Between 10 to 1:1.
Molar ratio between ATIII and factor II further preferably in 1:30 between 1:2, preferably 1:28 to 1:2 it
Between, in 1:25 between 1:2, in 1:24 between 1:2, in 1:23 between 1:2, in 1:22 between 1:2, in 1:21 to 1:
Between 2, in 1:20 between 1:2, in 1:18 between 1:2, in 1:15 between 1:2, in 1:12 between 1:2, or 1:
Between 10 to 1:2.
Other details for the treatment of method according to the present invention are described further below.
The molar ratio that following assumed value calculates ATIII and FII is preferably based in the application:
Molecular weight=58,000Da of-ATIII
Molecular weight=72,000Da of-FII
Plasma concentration=2.4 μm the ol/L (health volunteer) of-ATIII
Plasma concentration=1.4 μm the ol/L (health volunteer) of-FII
- 1IU/kg ATIII=140 μ g/kg=2.4 nanomole/kilogram ATIII
- 1IU/kg FII=90 μ g/kg FII=1.25 nanomole/kilogram FII
- 1IU ATIII:1IU FII is equal to 1.92 moles of ATIII:1 moles of FII, therefore is approximately equal to 2 moles of ATIII:1 and rubs
You are FII.
Heparin
" heparin " according to the present invention is functional heparin, the functional heparin of the i.e. purifying especially separated.It is functional
Heparin shows the bioactivity of the co-factor of ATIII.Heparin and HSPG (hepatose protein sugar) be used separately as ATIII drug and
Physiology co-factor.Functional heparin of the invention includes this field also it is known that being suitable for activating the specificity penta of ATIII
Polypeptide sequence.ATIII is accelerated the suppression speed of fibrin ferment, activation factor X (FXa) and activation factor IX (FIXa) by heparin.
Functional heparin can be selected from unfraction heparin (UFH), low molecular weight heparin (LMWH) and synthesis pentasaccharide factor Xa
Inhibitor or their mixture.UFH is the heparin for the preferred type of purposes described herein.For mediated by heparin
ATIII is activated to inhibit FXa, and the specific pentasaccharide sequence sufficiently meets.However, in order to accelerate the fibrin ferment of ATIII to press down
System, needs the heparin of at least 18 Heparin units.UFH is the heparin for the preferred type of purposes described herein, especially
It is when being contemplated by heparin amplification ATIII fibrin ferment inhibition.
Coagulation factor substitute products according to the present invention may include heparin, wherein preferably providing heparin in the product has
Between 0.1-10IU/mL, in 0.2-5.0IU/mL time, in 0.2-3.0IU/mL time and preferably 0.4-2.0IU/mL it
Between activity level.
Albumin
Coagulation factor substitute products according to the present invention can also include albumin.
The albumin of (purifying) that albumin according to the present invention especially separates.Albumin is preferably human albumin.
Albumin is preferably protein derived from blood plasma.
Blood loss
Blood loss use herein is the total blood volume from tissue damage acquired during the observation period.
Thrombus scoring
Thrombus scoring used herein describe after vein smoulders 30 minutes derived from the vein segment of incision thrombus/
The size and degree of thrombus.Thrombus scoring is used as the substitute marker of thromboembolic events risk.
Scoring 0-is without thrombus
Score 1-one or several microthrombus, weight in wet base immeasurability
Score 2-one or several thrombus, and weight in wet base can measure
Score 3-entirely shutting property thrombus
Wet weight of thrombus
Wet weight of thrombus describes vein and smoulders 30 minutes later from the weight in wet base of the thrombus for the vein segment cut, and further characterizes
The thrombus detected.
D-dimer
D-dimer (or D dimer) is fibrin degradation product (FDP) (or FDP), i.e., blood clotting passes through plasmin
It is present in the little albumen matter segment in blood after solution degradation.D-dimer is not present usually in human plasma, in addition to blood coagulation system
Other than being activated, such as since there are thrombosis or disseminated intravascular coagulations (DIC).
Reach the time of hemostasis
The time for reaching hemostasis describes from tissue damage to the complete time for stopping bleeding within the applied observation period,
And it is used as the direct indicator of the hemostasia effect of tested intervention.
Acquired coagulation factor deficiency
Acquired coagulation factor deficiency according to the present invention is especially acquired factor composite factor and lacks, preferably by
Vitamin K deficiency or excessive oral anticoagulant agent cause.It may be liver function energy barrier that the synthesis of factor composite factor is impaired
Hinder or the result of liver transfer operation.When patient's bleeding or intention are performed the operation, treatment as described in this application is especially advantageous.Institute
In the case of having these, it may be useful for applying coagulation factor substitute products of the invention.Take the patient of oral anticoagulant
It shows increased thromboembolism tendency, therefore there is special advantage with coagulation factor substitute products treatment of the invention, because
To describe the reduction of patient's thromboembolic complication risk in the application.For the present invention, oral anticoagulant is especially wrapped
The antagonist of K containing oral vitamin or the oral anticoagulant (DOAC/NOAC) directly acted on.
It can be disseminated intravascular coagulopathy according on the other hand acquired coagulation factor deficiency according to the present invention
(DIC) as a result, also referred to as consumption coagulopathy.DIC is a kind of pathologic process, it is characterised in that the extensive of coagulation cascade swashs
It is living, cause to form blood clot and fibrinous generation and deposition in the thin vessels of entire body.This may cause respectively
It plants the microvascular thrombosis in organ and leads to multiple organ dysfunction syndrome and multiple organ failure.In addition, due to process of setting
Coagulation factor and blood platelet are consumed, so normal coagulation is impaired and diffusivity bleeding may occur from each position.Fiber egg
The disorder of white dissolution system further results in intravascular grumeleuse and is formed, but in some cases, and accelerating fibers protein dissolution can also
It can lead to severe haemorrhage.International thrombosis and DIC sub-committee, hemostasis association propose DIC defined below: " one kind obtains
Obtain property syndrome, it is characterised in that the intravascular activation for the blood coagulation that limitation caused by due to different is lost.It may rise
It is damaged derived from microvasculature and to it, if serious enough, may result in organ dysfunction."
DIC itself will not occur, and be intended only as the complicated factor of another potential illness, usually suffer from serious disease
People.Other than the mortality risk as caused by potential disease, extensive be lost of tissue blood flow causes with the combination of bleeding simultaneously
Mortality risk increases.However, existing concentrate of coagulation factors well known in the prior art is not recommended for the clinical setting.According to
On the other hand, when applying conventional coagulation factor substitute products known in the art-at least if applied with high dose, seen
Patient can be reduced by application coagulation factor substitute products according to the present invention by, which observing, occurs the risk of DIC or DIC occurs
The risk of sample symptom, i.e. molar ratio between ATIII and factor II are at least 1:30.
The congenital deficiency of coagulation factor
For the present invention, congenital factor lacks the factor composite factor shortage that can be any patient,
Especially congenital coagulation proenzyme lacks or congenital factor X lacks.In addition, for the present invention, coagulation factor it is congenital
Lacking can be the factor composite factor of any patient in clinical setting and lacks, wherein do not indicate other treatment measure or
Expected therapeutic effect is not caused.One non-limiting example can be when specific coagulation factor or inhibitor concentrate are unavailable
When emergency.The example of birth defects is hemophilia B, and congenital factor VII lacks or congenital lack of protein c.?
It may need to stop or prevent the bleeding of these patients in the situation.For the present invention, bleeding can be apparent bleeding
Or bleeding after peri-operation period or traumatic event.In all of these situations, it can indicate to apply coagulation factor substitution of the invention
Product.
Thromboembolic complication
Thromboembolism includes two illnesss that are mutually related, they are the parts of same pedigree, i.e. deep vein thrombosis shape
At (DVT) and pulmonary embolism (PE).Spectrum of disease is from clinically unsuspected to clinically inessential to leading to dead a large amount of bolts
Plug variation.According to Virchow trias, three factors are important that (1) impaired blood flow is (strongly fragrant in the generation of thrombosis
Product), (2) injury of blood vessel, and (3) blood change (hypercoagulability).The change of blood is also possible to drug-induced.Of the invention
Coagulation factor substitute products can be used for treating any one of the illness.By applying product of the invention, patient is reduced
The risk of thromboembolic complication.
Wound/multiple wound
For the present invention, the damage of wound being preferably characterized in that several (> 1) physical regions or tract, it is special
In the case where not being the combination threat to life at least one damage or several damages, especially in injury severity scale
(ISS) severity > 16 on scale.According to definition, multiple outer wound response is distinguished with a variety of injuries, these injuries will not
Threat to life.Coagulation factor substitute products of the invention can be preferred for treating any one of the illness.
The coagulopathy that wound induces
Haemorrhagic shock caused by blood loss is the major reason of major injuries death.The bleeding of life-threatening it is potential
Pathological Physiology is usually caused by the combination of traumatic damage and coagulopathy.The reason of coagulopathy is multifactor and interrelated
's;These include the consumption and dilution of coagulation factor and blood platelet, the dysfunction of blood platelet and blood coagulation system, plasmin
Solution increases, and passes through blood coagulation system disorder and hypocalcemia caused by infusion solution (crystalloid and colloid).
In addition, the acute intrinsic coagulation disease occurred in the trauma patient of major injuries is referred to as the blood coagulation of wound-induced
Sick (TIC), and be the urgent property that tissue damage and Low perfusion lead to blood loss.Facilitate TIC mechanism include it is anticoagulant, disappear
Consumption, dysfunction of platelet and fibrinolysis.Coagulation factor substitute products of the invention are preferably used to treat the disease
Any one of disease.
Big bleeding/obvious bleeding
Any kind of bleeding can be the illness that product of the invention can be treated suitably.Bleeding is cured by U.S.'s surgery
The advanced wound life of Shi Xuehui supports (ATLS) to be divided into four classes (Manning, JE " Fluid and Blood
Resuscitation"in Emergency Medicine:A Comprehensive Study Guide.JE Tintinalli
Ed.McGraw-Hill: New York 2004.p227).Due to traumatic damage, potential medical conditions or combinations thereof and show
Blood.Coagulation factor substitute products of the invention are preferably used to treat any one of the illness.For characterizing the art of bleeding
The big bleeding of language, obvious bleeding, serious and significant bleeding are in this application with synonymous use.
Therefore, coagulation factor substitute products of the invention can preferably projector treat or prevent have acquired blood coagulation because
The patient's bleeding that there is congenital factor to lack for the patient's bleeding of sub- deficiency disease and/or treatment or prevention.
More specifically, coagulation factor substitute products of the invention are preferably used to treat or prevent one or more illnesss,
It is selected from wound;Multiple wound;Coagulopathy caused by wound;Main obvious serious or significant bleeding;It is any kind of
Wound associated coagulopathies;Perioperative bleeding following associated coagulopathies;Be deficient in vitamin K dependence coagulation factor;Acquired blood coagulation barrier
Hinder, such as liver diseases etc.;Hemophilia B;Use the hemophilia B of inhibitor;Received oral vitamin K antagonist or straight in the past
It connects effect oral anticoagulation (DOAC/NOAC) treatment and needs quickly to reverse vitamin K antagon or the anticoagulation of DOAC/NOAC
The patient of effect;Significant bleeding, such as peri-operation period, it is related with vitamin K-dependent clotting factor shortage after wound etc.,
Especially external vitamin K is anticoagulant outer;And combinations thereof.
Effect
Coagulation factor substitute products of the invention are characterized in that it shows enough effects.The effect of product, is preferred
And have effects that suitable lower than the reference coagulation factor substitute products of molar ratio between the ATIII and factor II of 1:30.It is excellent
Selection of land, " suitable " expression effect is identical or more preferable in the context of this application, or the only appropriateness drop compared with the Reference Product
It is low.Reference therapy of the molar ratio lower than 1:30 or Reference Product between ATIII and factor II include controlling for basic not ATIII
Treatment or product.
For the present invention, effect especially can be quantified or be expressed by blood loss, preferably pass through blood loss certain
It reduces to quantify.
It can quantify or express by the value of bleeding stopping period according to effect on the other hand of the invention, preferably by reaching
Certain reduction to the time value of hemostasis indicates.
It can quantify or express by the value of survival probability after damage according to effect on the other hand of the invention.
Compared with blood loss with placebo treatment or after not treating, reduced with the blood loss of patient after product treatment,
Middle blood loss be preferably decreased to placebo treatment blood loss is bright or blood loss after not treating 75% or less, lower than 70%, it is low
In 60%, lower than 55%, lower than 50%, lower than 45%, lower than 40% or be lower than 35%.Therefore, the effect of product of the present invention with
Even it is sufficient improve that the reference substance, which is compared,.
When compared with reference therapy, the blood loss of patient is substantially the same after being treated with the product or only appropriateness increases,
Or wherein compared with reference therapy, the blood loss of patient is reduced.Preferably, compared with referring to treatment, after product treatment
The blood loss of patient reduces at least 5%, at least 10%, at least 15% or at least 20%.The reference therapy is controlled with described
Treat identical, the molar ratio between the ATIII and factor II of the product used in the reference therapy is lower than other than 1:30.Cause
This, compared with the reference substance, even it is to improve that the effect of product of the invention, which is sufficient,.
If only appropriateness is increased for the blood loss of patient after with product treatment compared with the blood loss of reference therapy
In the case of, the appropriate incrementss amount to 60%, are no more than 50%, being no more than 40%, being no more than 30%, being no more than 20%,
No more than 15%, it is no more than 10% or is no more than 5%, wherein the reference therapy is identical as the treatment, in addition to described
Molar ratio between the ATIII and factor II of product used in reference therapy is lower than other than 1:30.
Preferably, compared with reaching the time value of hemostasis after not treating with placebo treatment or, with patient after product treatment
The time value for reaching hemostasis reduces, wherein being treated compared with the value after placebo treatment or without the time value for the treatment of with the product
The time value for reaching hemostasis afterwards is preferably reduced to few 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least
50%, at least 55% or at least 60%.Therefore, even being sufficient improve compared with the reference substance the effect of product of the present invention
's.
It is further preferred that reaching the time value of hemostasis substantially with patient after product treatment compared with reference therapy
Identical or only appropriateness increase, or wherein compared with reference therapy, subtracted with the time value that patient after product treatment reaches hemostasis
It is small, it is preferable that compared with the value after reference therapy, be reduced at least 5% with the time value that patient after product treatment reaches hemostasis,
At least 10%, at least 15% or at least 20%, wherein the reference therapy is identical as the treatment, in addition to the reference is controlled
Molar ratio between the ATIII and factor II of product used in treatment is lower than other than 1:30.Therefore, compared with the reference
When, even it is to improve that product of the invention, which is at least enough,.
If the time value that patient reaches hemostasis after with product treatment only moderately increases compared with reference therapy,
Then described value appropriateness increase amount to be no more than 80%, be no more than 70%, be no more than 60%, be no more than 50%, be no more than 40%,
No more than 30%, it is no more than 20% or is no more than 10%, wherein the reference therapy is identical as the treatment, in addition to described
Molar ratio between the ATIII and factor II of product used in reference therapy is lower than other than 1:30.
The survival probability of patient is preferably essentially identical with the probability survived after reference therapy after being treated with product of the present invention.Institute
The reference therapy stated is identical as the treatment, in addition to the product used in the reference therapy ATIII and factor II it
Between molar ratio be lower than 1:30.Preferably, patient is being substantially 100% with the survival probability after product treatment of the invention.
Safety
Coagulation factor substitute products of the invention or treatment method according to the present invention are characterized in that it shows to improve
Safety, that is, reduce the risk of patient's thromboembolic complication.
Compared with the safety of Reference Product or reference therapy, the safety of product of the invention or treatment is especially changed
Kind, Reference Product or reference therapy are identical as the product or treatment, in addition to the molar ratio between ATIII and factor II is lower than 1:
30。
For the present invention, safety particularly can be quantified or be expressed by the value of fibrin ferment generation, preferably be passed through
Certain reduction that fibrin ferment generates quantifies, certain reduction of the value of potentiality power (ETP) is generated especially by fibrin ferment.
For the present invention, safety can particularly quantify or be expressed as the value of d-dimer concentration (DD), preferably
It is indicated by certain reduction of d-dimer concentration.
It can further quantify or express safety of the invention by the value of blood samples of patients fibrinogen concentration.
Preferably, compared with the value that the fibrin ferment of reference therapy generates, with the fibrin ferment of the patient after the processing treatment
The value of generation reduces at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, until
Few 40%, at least 45% or at least 50%, especially 1 hour, 2 hours and/or 3 hours after the production application product when, wherein
The reference therapy is identical as the treatment, in addition to product used in the reference therapy ATIII and factor II it
Between molar ratio lower than other than 1:30.Fibrin ferment, which generates, particularly generates potentiality (ETP) expression by fibrin ferment.
Preferably, compared with reference therapy, d-dimer concentration (DD) value of patient is reduced after being treated with product of the present invention
At least 1.5 times, at least 2 times, at least 2.5 times, at least 3 times, at least 3.5 times, at least 4 times, at least 4.5 times, at least 5 times, at least
5.5 times, at least 6 times, at least 6.5 times, at least 7 times, at least 8 times, at least 9 times, or at least 10 times, wherein the reference therapy
It is identical as the treatment, in addition to the molar ratio between the ATIII and factor II of product used in the reference therapy is lower than
Other than 1:30.The DD is reduced preferably at about 1 hour after applying product of the present invention, about 2 hours, about 3 hours and/or or about 4
It is realized when hour.
Preferably, compared with the blood fibrinogen concentration after reference therapy, patient's blood after being treated with product of the present invention
At least 1.5 times of the value increase of liquid fibrinogen concentration, at least 2 times, at least 3 times, at least 4 times, at least 5, at least 7.5, or extremely
It is 10 times few, wherein the reference therapy is identical as the treatment, in addition to the ATIII of product used in the reference therapy
Molar ratio between factor II is lower than other than 1:30.After being treated with product of the present invention the fibrinogen concentration value of patient with
Fibrin original content after placebo treatment or without treatment is essentially identical.
According to another aspect of the present invention, other than treating patient with product of the invention, patient also in advance, simultaneously or
It is then treated with substitute products (such as cold hypostasis) or with fibrinogen concentrate, it is preferable that in 5 mg/kgs and 150
Between mg/kg weight, between 10 mg/kgs and 100 mg/kg weight, preferably in 20 mg/kgs to 80 millis
Fibrin commercial weight application substitute products or fibrinogen concentrate between g kg weight.
According to further preferred aspect, patient is general in product of the invention and the survival after fibrinogen co-therapies
Rate is higher than the survival probability after reference co-therapies.The reference co-therapies are identical as the treatment, in addition in the reference
Molar ratio between the ATIII and factor II of product used in co-therapies is lower than 1:30.Preferably, patient is described with this
Survival probability after the product and fibrinogen of invention are cooperatively treated is substantially 100%.
According to further preferred aspect, the pulmonary arterial pressure of patient after product of the invention and fibrinogen co-therapies
Lower than pulmonary arterial pressure of the patient after reference co-therapies.The reference co-therapies are identical as the treatment, in addition in institute
The molar ratio between the ATIII of product used in reference co-therapies and factor II is stated lower than 1:30.Particularly, in the present invention
Product and fibrinogen co-therapies after there is no occur increase patient pulmonary arterial pressure.
According to further preferred aspect, promote blood coagulation with thrombin time (PT) value and/or activated partial of reference therapy
Proenzyme kinases time (aPTT) value is compared, and is promoted with thrombin time (PT) value and/or activated partial of patient after product treatment
Partial thromboplastin time (aPTT) value reduces at least 1.5 times, at least 2.0 times, at least 2.5 times, at least 3.0 times, at least 3.5
Times, at least 4.0 times, at least 4.5 times, at least 5.0 times, at least 7 times or at least 10 times, wherein the reference co-therapies with it is described
Treat it is identical, in addition to the molar ratio between the ATIII and factor II of the product used in the reference co-therapies be lower than 1:
30.Occur within about 1 hour, about 2 hours, about 3 hours and/or about 4 hours after the analog value of the PT or aPTT is particularly applied.
According to further preferred aspect, and after placebo treatment or (PT) value of the thrombin time without treatment and/or work
When the analog value of change partial thromboplastin time (aPTT) is compared, with the thrombin time of patient after product treatment
(PT) value and/or activated partial factor I time (aPTT) value are essentially identical and/or maximum inclined with described value
Difference, on condition that the maximum deviation is no more than 5.0,3.0,2.5,2.0 or 1.5 times.The analog value of the PT or aPTT is particularly
Occur at about 1 hour after application, about 2 hours, about 3 hours and/or about 4 hours.
According to further preferred aspect, with thrombin time (PT) value and/or activation of patient after product treatment
Partial thromboplastin time (aPTT) value is held substantially constant, and preferably after application about 1 hour, about 2 hours, about 3
After hour and/or administration in about 4 hours time limits.According to further preferred aspect, with patient after product treatment
Thrombin time (PT) value and/or the variation of activated partial factor I time (aPTT) value are no more than 10 times, 8 times, 6
Times, 5 times, 4 times, 3 times, 2.5 times, 2 times or 1.5 times, preferably after application about 1 hour, about 2 hours, about 3 hours and/or about 4 small
When time limit in.
The safety of PT and aPTT about product of the present invention being surprisingly found that with product and effect are related, especially
It is that the improvement of safety and effect with product is related.
According to another aspect, for the present invention, safety can be by thrombus score value as thromboembolic events wind
The surrogate markers of danger quantify or indicate, are preferably indicated by certain reduction that thrombus scores.Preferably, when as substitution mark
When remembering object, at least 0.5 point is reduced compared with the thrombus score value of reference therapy with the value that thrombus after product treatment scores,
At least one point, at least 1.5 points or 2 points.In addition to the product used in the reference treatment ATIII and factor II it
Between molar ratio lower than except 1:30, the reference treatment is identical as the treatment.
Pharmaceutical composition
The treatment preparation of coagulation factor and ATIII composition of the invention is suitable for the sheet of method described herein
Invention product can be prepared into lyophilized preparation or aqueous solution by mixing coagulation factor for storage, if co-formulation, have the phase
Hope the ATIII of purity and the optional pharmaceutically acceptable carrier that this field typically uses, excipient or stabilizer (all
These are known as " carrier " in this application) on duty together, i.e. buffer, stabilizer, preservative, isotonic agent, nonionic detergent,
Antioxidant and other various additives.Referring to Remington's Pharmaceutical Sciences, the 16th edition (Osol,
ed.1980).Under dosage and concentration used, these additives must be nontoxic to recipient.Therefore, product of the invention is special
It is not to be provided as the liquid of freeze-drying prods or stable storing.The optional pharmaceutically acceptable carrier, excipient or steady
Determine agent preferably to exist, condition is that they are approved for treatment animal or people, is preferred for treating people.
Buffer helps for pH to be maintained close in the range of physiological condition.They can be with about 2mM to about 50mM's
Concentration exists.Suitable buffer includes organic acid and inorganic acid and its salt, such as citrate buffer agent (for example, citric acid
One sodium-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-sodium dihydrogen citrate mixture etc.), amber
Hydrochlorate buffer is (for example, one sodium salt mixt of succinic acid-succinic acid, succinic acid-sodium hydroxide mixture, succinic acid-succinic acid
Disodium mixture etc.), tartrate buffer (such as tartaric acid-sodium tartrate mixture, tartaric acid-potassium tartrate mixture, wine
Stone acid-sodium hydroxide mixture etc.), fumarate buffer (such as one sodium mixture of fumaric acid-fumaric acid, fumaric acid-fumaric acid
Disodium mixture, one sodium of fumaric acid-Disodium fumarate mixture etc.), gluconate buffer (such as gluconic acid-glucose
Sour sodium mixture, gluconic acid-hydroxide mixture, gluconic acid-K-IAO mixture etc.), oxalic acid salt buffer
(such as oxalic acid-sodium oxalate mixture, oxalic acid-sodium hydroxide mixture, oxalic acid-potassium oxalate mixture etc.), lactate buffer is (such as
Lactic acid-sodium lactate mixture, lactic acid-sodium hydroxide mixture, lactic acid-potassium lactate mixture etc.) and acetate buffer (such as second
Acid-sodium acetate mixture, acetic acid-sodium hydroxide mixture etc.).Further, it is possible to use phosphate buffer, histidine buffering liquid
With front three amine salt such as Tris.
Preservative can be added to prevent microorganism from growing, and can be added with the amount of 0.2%-1% (w/v).It is suitble to
Preservative include phenol, benzylalcohol, metacresol, methyl p-hydroxybenzoate, propylparaben, octadecyldimethyl
Benzyl ammonium chloride, benzalconium halide (such as chloride, bromide and iodide), bistrium chloride and para hydroxybenzene first
Acid alkyl ester such as methyl p-hydroxybenzoate or propylparaben, catechol, resorcinol, cyclohexanol and 3- amylalcohol.
The isotonic agent of sometimes referred to as " stabilizer " can be added to ensure the isotonicity of liquid composition, and including polyalcohol sugar alcohol, preferably
Ternary or more advanced sugar alcohol, such as glycerol, erythrite, arabite, xylitol, sorbierite and mannitol.Stabilizer
Refer to that extensive types of excipient, envelop of function can dissolve therapeutic agent or help to prevent from filler to additive
It is only denaturalized or adheres on chamber wall.Typical stabilizer can be multi-sugar alcohol (listed above);Amino acid, such as arginine,
Lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-Leu, 2- phenylalanine, paddy ammonia
Acid, threonine etc., organic sugar or sugar alcohol, such as lactose, trehalose, stachyose, mannitol, sorbierite, xylitol, ribitol,
Myoinisitol, galactitol, glycerol etc., including cyclic alcohol as such as inositol;Polyethylene glycol;Amino acid polymer;Sulfur-bearing
Reducing agent, such as urea, glutathione, lipoic acid, sodium thioglycolate, thioglycerol, α-thioglycerol and sodium thiosulfate;Low point
Son amount polypeptide (for example, 10 residues or less peptide);Protein such as human serum albumins, bovine serum albumin(BSA) or are exempted from gelatin
Epidemic disease globulin;Hydrophilic polymer, such as polyvinylpyrrolidone monosaccharide, such as xylose, mannose, fructose, glucose;Disaccharides, such as
Lactose, maltose, sucrose;And trisaccharide, such as gossypose;And polysaccharide, such as glucan.Stabilizer can be with every parts by weight of activated albumen
The range of matter 0.1-10,000 weight exist.
Nonionic surfactant or detergent (also referred to as " wetting agent ") can be added to help dissolution treatment agent and guarantor
Aggregation of the human cytokines from resisting agitation induction is protected, this, which also allows preparation to be exposed to shear surface stress, not will lead to albumen
Qualitative change.Suitable nonionic surfactant includes polysorbate (20,80 etc.), poloxamer (polyoxamer)
(184,188 etc.), pluronic polyols, polyoxyethylene sorbitan monoether (- 20,- 80 etc.).Nonionic surfactant can about 0.05mg/ml to about 1.0mg/ml range exist, or
Exist with the range of about 0.07mg/ml to about 0.2mg/ml.
In addition other optional excipient include filler (such as starch), chelating agent (such as EDTA), antioxidant
(such as ascorbic acid, methionine, vitamin E) and cosolvent.
It is preferred that being configured to pharmaceutical composition by intravenously applying.
Drug products comprising antiprothrombin III (ATIII) are with described herein comprising factor (factor II)
The combined administration of product be one aspect of the present invention.It is provided according to another aspect, comprising factor (factor II)
Drug products are used to be administered in combination with the product comprising Antithrombin III (ATIII).Another aspect of the present invention relates to (i)
Treat or prevent with acquired coagulation factor deficiency patient bleeding or (ii) treat or prevent have congenital coagulation because
The method of the bleeding of the patient of sub- defect;By by coagulation factor substitute products as described above be applied to the patient come into
Row.Particularly, in the case where rear three aspects of the invention, ATIII and factor II can be arranged and/or provide for same
When use, be used alone or successively use.
" using simultaneously " in the sense of the present invention refer to by include at least separation as blood coagulation defined herein because
The composition of sub- FII and composition mixing comprising isolated ATIII, are then applied to patient as mixture.
" exclusive use " in the sense of the present invention refers to the coagulation factor as described in this application including at least separation
The composition of FII and composition comprising isolated ATIII are simultaneously or separately in turn applied, and thus the sequence of the application is not
It is related.
" successively using " in the sense of the present invention means the coagulation factor as described in this application than including at least separation
The composition of FII and composition separate administration comprising isolated ATIII, it is thus unrelated with the sequence of the application, and by
Time interval between this is administered twice is no more than 2 days, and preferably more than 1 day, more preferably no more than 4 hours do not surpass most preferably
Spend 1 hour.
The composition is provided typically as a part for the sterile pharmaceutical composition for including pharmaceutically acceptable carrier.
The composition can be any suitable form (depending on being applied the desired method of patient).
Determine dose population and time limit treatment time completely in the ability of those skilled in the art with composition of the invention
In range.The dosage of product of the present invention to be administered depends on weight and/or existing anticoagulant or coagulopathy degree.
It is also conceivable to the severity of the illness is with determination product of the invention or the suitable dosage of composition.
It will be understood by those skilled in the art that the present invention described in this application is easy to other than those of specific descriptions
It is changed and modifies.It should be understood that the present invention includes all such changes and modifications fallen within the spirit and scope of the invention.This
Invention further includes the either individually or collectively all features for referring to or pointing out in the application, composition, step and compound, and
The feature, composition, any and all combinations of any two in step and compound or more.
Certain embodiments of the present invention are described referring now to following embodiment, the mesh that these embodiments are given for example only
, it is not intended to limit general range described above.
Embodiment-Rabbit Model
The hemostasia effect of PCC in the Rabbit Model of bleeding and tissue damage that hemodilution mediates
Material and method
Animal
By the 3-4 month female CHB rabbit of weight 2.8-4.0kg (Manfred Bauer, Neuenstein-Lohe,
Germany) every cage one is only placed in wire basket, 21-23 DEG C and 50% relative humidity, 12h/12h light-dark cycle.It is arbitrarily mentioned to animal
For tap water and feeding rabbit particle (Deutsche Tiernahrung Cremer GmbH&Co.KG,
Duesseldorf, Germany).All animals receive nursing according to " European animal protection and research pact ", and the research
The approval of the committee, organizational ethics is arrived.
Hemodilution
All treatments carry out in anesthetized animal.Pass through the combination induced anesthesia of ketamine and Xylazine and passes through sucking
Isoflurane anesthesia maintenance.Then animal intubation is placed in ventilator (Heyer Access, Heyer Medical AG, Bad
Ems, Germany) on.
By extracting 30mLkg-1 blood and being transfused the pre- 30mLkg-1 hydroxyl second for being warmed to 37 DEG C from arteria carotis
Base starch (HES) 200/0.5 (Infukoll 6%, Schwarz Pharma AG, Mannheim, Germany), respectively to animal into
Row hemodilution (Fig. 1).The process was repeated at 45 minutes.At 30 minutes, between blood drawing twice and HES infusion circulation
Interim, animal receive the red blood cell of 15mLkg-1 supplement, by being centrifuged 10 minutes whole family rabbits from taking-up with 800 × g
Blood preparation, with brine and is resuspended in ringer lactate, applies into vena jugularis externa.
Injury of kidney
The 60min after starting hemodilution is applied on the outside at renal plevis with the scalpel form of cut or cuts of 15mm long and 5mm depth
Standardized injury of kidney (Fig. 1).
Treatment
Animal is randomly assigned to be immediately subjected to intravenously apply isotonic saline solution (placebo), agent before the damage of kidney notch
Amount be 25IU/kg PCC (CSL Behring GmbH, Marburg, Germany), dosage is
11.5IU/kg ATIII (CSL Behring GmbH, Marburg, Germany) or PCC 25IU/kg+
The combined therapy (Fig. 1) of 11.5 or 23IU/kg ATIII.Experimental group is respectively made of 6-7 rabbit.If not stated otherwise,
The PCC used in all embodiments includes low-level ATIII, that is, the molar ratio shown between ATIII and factor II is lower than
1:30.For PCC used in reference purpose embodiment, also referred to as " conventional PCC " or only " PCC " comprising ATIII and factor II
Between molar ratio be lower than 1:30.ATIII level liter of the invention is realized by the way that the ATIII of corresponding additional quantity is administered in combination
Height, i.e. molar ratio between ATIII and factor II are at least 1:30, and the ATIII represents " improved PCC " of the invention.
The activity level provided in IU for the PCC of application refers to the caling factort IX content of PCC.One international unit
(IU) activity is equivalent to the amount of corresponding coagulation factor in 1mL human normal plasma.The routine that uses in embodiment and improved
PCC shows factor II content, essentially identical based on the activity level provided with IU and factors IX content.Thus, for example
The combined therapy of 50IU/kg routine PCC and 25IU/kg ATIII will lead to the molar ratio between the ATIII of application and factor II
It is about 1:1.For calculating the molar ratio in modification PCC between ATIII and factor II, provided in routine PCC as used herein
Low-level ATIII can ignore.
Conventional and improved PCC used in embodiment shows the heparin content of about 1IU/ml.
Terminal
Hemodilution, treatment, experimental injury of kidney and haemostatic effect assessment research method example in Fig. 1 (abbreviation:
HES, hydroxyethyl starch;PCC (prothrombin complex concentrate), ATIII (Antithrombin III)).Primary endpoint be
The time (Fig. 1) of hemostasis and blood loss is observed within 30 minutes after standardization kidney notch damage.Be up to hemostasis timing definition be from
The interval that bleeding or oozing of blood of the kidney notch to observable stop.Blood loss is by aspirating the blood volume acquired from cutting part.
Blood loss in 30 minutes is immediately begun to after lancing and reaches the observation period of the time of hemostasis.
As a result
It is dilute in blood after illustrating the combined therapy with salt water (placebo), PCC, ATIII or PCC and ATIII in Fig. 2
Total blood loss after the rabbit Plays injury of kidney released.Shown data represent intermediate value and range.The abbreviation used is PCC (solidifying
Hemase original compound concentrate) and ATIII (Antithrombin III).As shown in Figure 2, the PCC that dosage is 25IU/kg can be incited somebody to action
Total blood loss intermediate value after standardizing injury of kidney from 94mL, (treat by isotonic saline solution;Placebo) it reduces to 34mL.PCC(25IU/
) and ATIII kg (11.5 or 23IU/kg, being equivalent to molar ratio between ATIII and factor II is respectively about 1:1 and about 2:1)
It is respectively 55 and 38mL that combination, which can also be reduced total blood loss to intermediate value,.Individual ATIII (11.5IU/kg) does not have blood loss
Any relative influence.
It is illustrated in Fig. 3 after the combined therapy with salt water (placebo), PCC, ATIII or PCC and ATIII, in blood
Reach the time of hemostasis after diluted rabbit Plays injury of kidney.The data of display indicate intermediate value and range.The abbreviation used
It is PCC (prothrombin complex concentrate) and ATIII (Antithrombin III).Dosage is that the PCC of 25IU/kg can reduce mark
From (the isotonic saline solution processing of 30 minutes maximum observation periods after standardization injury of kidney;Placebo) to 10 minutes realize hemostasis time.PCC
(11.5 or 23IU/kg, the molar ratio being equivalent between ATIII and factor II are respectively about 1:1 peace treaty by (25IU/kg) and ATIII
It is respectively 16 and 17 minutes that bleeding stopping period can also be foreshortened to intermediate value by combination 2:1).Independent ATIII (11.5IU/kg) is to reaching
Time to hemostasis does not have any relative influence (Fig. 3).
Vein smoulders ATIII in Rabbit Model (the Wessler model of improvement) and is administered in combination to the thrombotic of PCC
It influences
Material and method
Animal
2.2-3.2kg of weight 3-4 month female New Zealand white rabbit (Manfred Bauer,
Neuenstein-Lohe, Germany) compliance " European animal protection and research pact " receives nursing and the research has obtained locality
Government administration section approval.Animal is respectively resided in wire cage, 21-23 DEG C and 50% relative humidity, 12h/12h light-
The dark period.Tap water and feeding rabbit particle (Deukanin, Deutsche Tiernahrung are arbitrarily provided to animal
Cremer GmbH&Co.KG, Duesseldorf, Germany).All animals connect according to " European animal protection and research pact "
It is nursed, and the research has obtained the approval of the committee, organizational ethics.
Treatment
Animal is randomly assigned with receive intravenous application and 7-138IU/kg ATIII (CSL
Behring GmbH, Marburg, Germany)) combination dosage be 300IU/kg PCC (
CSL Behring GmbH, Marburg, Germany).3 rabbit compositions of each freedom of experimental group.Only with isotonic saline solution (placebo) or
Only the animal of 300IU/kg PCC treatment is used as control.
The Wessler of improvement is tested
Operation carries out (ketamine/Xylazine) under deep anaesthesia.10 minutes induction veins smoulder after infusion.Pass through
Exposure opposite side jugular vein simultaneously separates the section of about 2cm to determine hemostasis effect, causes to smoulder completely in isolated section.?
It smoulders after inducing 30 minutes, cuts vein segment and dissected in sodium citrate solution.According to 0 to 3 points-scoring system to any sight
The thrombus observed is classified, and measures their weight in wet base.Thrombus is scored is defined as: 0 (no grumeleuse), 1 (one or a small number of small
It is grumeleuse, too small without can determine that weight), 2 (incomplete occlusive grumeleuses, with measurable weight) or 3 (what is entirely shut is solidifying
Block).
As a result
The rabbits after intravenous with the combined therapy of salt water (placebo), PCC or PCC and ATIII is illustrated in Fig. 4 a
Thrombus scoring after arteries and veins thrombosis.The data of display represent intermediate value and range.The abbreviation used is that (factor is compound by PCC
Object concentrate) and ATIII (Antithrombin III).As is shown in fig. 4 a, smouldering 30 minutes post doses in vein is 300IU/kg's
PCC causes scoring to be 2 thrombus, (suitable by the way that the ATIII that dosage is 28IU/kg, 69IU/kg and 138IU/kg is administered in combination
Molar ratio between ATIII and factor II is respectively about 1:5, about 1:2 and about 1:1), it completely inhibits vein and smoulders.Joint
The ATIII (molar ratio being equivalent between ATIII and factor II is about 1:20) of application 7IU/kg causes thrombosis part to subtract
Few, thrombus scoring is 1-2.
Similarly, wet weight of thrombus is reduced by the way that ATIII is administered in combination.Illustrated in Fig. 4 b with salt water (placebo),
Wet weight of thrombus after the rabbit medium sized vein thrombosis of the combined therapy of PCC or PCC and ATIII.The data of display represent intermediate value
And range.The abbreviation used is PCC (prothrombin complex concentrate) and ATIII (Antithrombin III).Such as institute in Fig. 4 b
Show, dosage is that the PCC of 300IU/kg leads to the wet weight of thrombus of about 18mg after vein smoulders 30 minutes, by the way that dosage is administered in combination
For 28IU/kg, 69IU/kg and 138IU/kg ATIII (being equivalent to molar ratio between ATIII and factor II is respectively about 1:
5, about 1:2 and about 1:1), reverse the vein to smoulder completely.The ATIII that dosage is 7IU/kg is administered in combination (to be equivalent to
Molar ratio between ATIII and factor II is about 1:20) cause the part of wet weight of thrombus to reduce.
Embodiment-pig model
Material and method
Animal and operation preparation
The research is based on experimental animal Nursing principles (Principles of Laboratory Animal Care)
Germany's legislation carries out.Official's license is authorized by corresponding government's animal care and using office.Disease-free breeding will be come from
The German native breed pig of facility raises at least 5 days in draft chamber to adapt to environment.Make their overnight fastings before surgery, with
Meaning drinking-water.
Initial drug: azaperone (4mg kg is applied by intramuscular injection-1) and atropine (0.1mg kg-1).Then it uses
Propofol (3mg kg-1) anesthesia, auris dextra intravenous administration is given by 18-G intubation intravenous injection.With pressure control mode with 20-22
Respiration rate per minute ventilates to animal, and tidal volume is 8mL kg-1, to keep paCO2Between 36 and 40mmHg, oxygen
Score is 0.21, then wound Cato, Draeger, Luebeck, Germany).It maintains to anaesthetize with isoflurane, end-tidal concentration is
1.2-1.4%, and constant infusion fentanyl (2 μ g kg-1h-1)。
Initial fluid therapy includes crystalloid solutions (2mL kg-1h-1).Blood temperature;Artery, central vein and pulmonary artery
Pressure;It is fought blood using standard Anesthesia Monitoring device (AS/3, Datex Ohmeda, Helsinki, Finland) constantly monitoring tail pulse
Oxygen measurement and electrocardiogram.
Two 8.5-Fr conduits are implanted into right side and left side jugular vein by surgical operation to carry out volume replacement, and by lung
Arterial duct is placed in wedge-shaped position by right side 8.5-Fr conduit.Hemodynamic is recorded by the 18-G conduit in right carotid artery
Learn variable.From all blood samples of arterial line extraction.
Damage and hemodilution
First injury stage includes 1.) bilateral closed femoral fracture, 2.) unilateral thorax is dampened, and uses stable breeding bolt
About 60% animal estimated blood volume (65ml/kg weight), rate 100mL/min are extracted in rifle induction and 3. controls.According to
Need to be transfused crystalloid to maintain mean arterial pressure (MAP) to be higher than 30mmHg.After about 20 minutes haemorrhagic shock phases, lead to
Crystalloid infusion compensation Volume Loss is crossed, and air-breathing oxygen mark is increased to 1.0.Second injury stage is lured by standardized blunt liver
It leads.After second of injured stage, second of shock (10 minutes) is carried out at once before application hemostasis is intervened.
Processing
10 minutes after second of wound, using sealing envelope, the list generated using the computer of 1:1:1:1 format is preceding
1 group be randomized to animal to looking forward or upwards property in lower column processing group:
1. the 1st group: control (placebo)
2. the 2nd group: PCC50IU/kg
3. the 3rd group: PCC50IU/kg+ antithrombase 50IU/kg (PCC+AT50 group)
4. the 4th group: PCC50IU/kg+ antithrombase 25IU/kg (PCC+AT25 group)
5. the 5th group: PCC50IU/kg+ antithrombase 12.5IU/kg (PCC+AT12.5 group)
6. the 6th group: 80 mg/kg p of PCC50IU/kg+ fibrinogen (PCC+Fib group)
7. the 7th group: 80 mg/kgs of PCC50IU/kg+ fibrinogen+antithrombase 50IU/kg (PCC+Fib+AT50
Group)
Therefore, test the molar ratio between following ATIII and factor II: in the 2nd group (PCC50IU/kg), ATIII with
Molar ratio between factor II is lower than 1:30, because applying individually routine PCC.2nd group (PCC50IU/kg) hereinafter
Referred to as PCC monotherapy.In the 3rd group (PCC+AT50 group), the 4th group (PCC+AT25 group) and the 5th group (PCC+AT12.5 group),
Molar ratio between ATIII and factor II is respectively about 1:0.5, about 1:1 and about 1:2.In the 6th group (PCC+Fib group),
Molar ratio between ATIII and factor II is lower than 1:30.In the 7th group (PCC+Fib+AT50 group), between ATIII and factor II
Molar ratio be about 1:0.5.ATIII, AT and antithrombase synonymously use.
For PCC substation, using four factor PCC (PN, CSL Behring, Germany) and antithrombase (CSL Behring, Germany).Observation period terminates for 240 minutes after damaging at second.Will it is entire this when interphase
The animal to survive in limit implements to be euthanized with amobarbital.It reopens abdomen immediately after execution, vena cava clamps is clipped in liver
On dirty, and intraperitoneal blood is collected to determine the total blood loss after damage.Several organs are taken out after death and are prepared for group
It knits to check.
Lab analysis
It collects blood and several time points after second of injury stage carries out arterial blood gas analysis.For after injury
Dead animal before 240 minutes, is finally assessed immediately after death.With blood gas analyzer (ABL825, Radiometer
GmbH, Willich, Germany) measurement oxygen and carbon dioxide pH and partial pressure, base excess and lactate.Use Standard blood credit
Analyzer (MEK-6108, Nihon Kohden, Tokyo, Japan) assesses platelet count and hemoglobin concentration.Factor
Time (PT), activated partial factor I time (aPTT) and fibrinogen concentration are made by standard laboratory methods
Steel ball coagulo meter (MC 4plus, Merlin are used with from Dade Behring (Dade Behring, Marburg, Germany)
Medical, Lemgo, Germany) it is appropriate test to determine.With from Dade Behring (Dade Behring, Marburg,
Germany) appropriate test assessment d-dimer.
The measurement of thrombus elastic force and fibrin ferment generate
Using Calibrated Automated Thrombogram (CAT, Thrombinoscope BV,
Maastricht, The Netherlands) measure in blood plasma including parameter fibrin ferment generate potentiality (ETP) including blood coagulation
Enzyme generates (Spronk HM et al. Thromb Haemost.2008;100:362-364.).With 20 μ L in 80 μ L plasma samples
Fluorogenic substrate and 20 μ L triggering reagent are assessed.Triggering reagent is 1pM tissue factor and 4 μM of phosphatide.Each fibrin ferment generates
Analysis in identical blood plasma with the caliberator of fixed amount (Thrombin Calibrator, Thrombin oscope BV,
Maastricht, Holland) obtain fluorescence curve calibrated.Using Ascent Reader (Thermolabsystems OY,
Helsinki, Finland) measurement fluorescence, and use the 4th edition software of Thrombinoscope (Thrombinoscope BV,
Maastricht, Holland) calculate fibrin ferment formation curve.
Pathological examination
After death, internal organs (heart, lung, liver and kidney) is taken out immediately and is fixed with the formalin of 10% buffering.It will
The hepatic portion of damage is cut into 3-mm- slab, and the virologist by being unaware for the treatment of is in naked eyes and test under microscope
To assess degree of injury.In addition, handling the representative histotomy of all 4 organs to determine the generation of thromboembolic events.
All samples are embedded in paraffin and are dyed by H&E and standard elastica van Gieson scheme, for aobvious in optics
Histological examination is carried out under micro mirror.Two kinds of colouring methods are applied to from the organized slice of institute.
Histological examination confirms the beneficial effect of the application of additional ATIII as described in this application (data are not shown).
Terminal
The primary endpoint of the research is the safety of the total blood loss (effect) and hemostasis intervention after reducing damage.It is secondary
Wanting terminal includes the influence to coagulation parameters.
As a result
Total blood loss in Fig. 5, after illustrating second of hepatic injury.With control group and monotherapy PCC50 treatment group
It compares, the combination of PCC and ATIII reduce blood loss.
As shown in Figure 5, in PCC+ antithrombase group, total blood loss after second of injury stage be (this research
Primary Endpoint) (653 ± 42mL of PCC+AT50 group;552 ± 31mL of PCC+AT25 group;548 ± 68mL of PCC+AT12.5 group) than single
One 50 groups of therapy PCC (907 ± 132mL) is lower.The total blood loss (719 ± 115mL) of PCC+Fib group is higher than PCC+Fib+
AT50 group (613 ± 34mL).Total blood loss highest (1671 ± 409mL of control group;Compared with all groups, P < 0.001).
In Fig. 6, survival data is expressed as Kaplan-Meier curve.PCC monotherapy and PCC+ antithrombase group
All animals survive (100%) within the complete observation period, and 2 (29%) (mean survival times in 7 in control group
210 minutes) after second of wound dead (Fig. 6).
According to the data presented in Fig. 6,5 animal (71%) Deaths in PCC+Fib group in 7 animals are (average
160 minutes time-to-live), and all PCC+Fib+AT50 treatment groups survival (100%).The morning of animal from PCC+Fib group
Phase death is the increase (120 minutes 26 ± 7mmHg of time point after second of wound) due to pulmonary hypertension.In Fig. 7
Show the data of average lung pressure (MPAP, (average value ± standard deviation)).Lung is not observed in PCC+Fib+AT50 group
The increase of angiosthenia is (for example, 120 minutes time points after second of wound, 16 ± 1mmHg;Fig. 7).
In fig. 8, antithrombase concentration (average value ± standard deviation) whithin a period of time is illustrated.Wound and blood loss
Property shock after, the antithrombase of all animals is down to 48 ± 9%.According to a group distribution, antithrombase substitution causes antithrombase dense
Degree increases (30 minutes: PCC+AT50 group 145 ± 12% after second of wound in dose dependent;PCC+AT25 group 94 ± 10%;
PCC+AT12.5 group 70 ± 5%;PCC+Fib+AT50 136 ± 17%) (Fig. 8).Antithrombase level in these animals is at any time
Between keep increase.In the animal of no antithrombin to treat, antithrombase is maintained at 41 after second of wound at 30 minutes ±
8% level, and 37 ± 11% level is maintained at after second of wound at 240 minutes.
In Fig. 9, it is shown that the fibrinogen concentration (average value ± standard deviation) changed over time.In wound and mistake
After courage and uprightness shock, the fibrinogen concentration in all animals is down to 60 ± 9mg/dL.According to a group distribution, fibrinogen substitution
The dose dependent of fibrinogen concentration is caused to increase (198 ± 16mg/dL of PCC+Fib group;PCC+Fib+AT50 group 202 ±
15mg/dL) (Fig. 9).Fibrinogen concentration in PCC+Fib+AT50 keeps stable at any time.In the animal of PCC50 treatment
In, the concentration of fibrinogen is reduced to 4 ± 8mg/dL at any time, and in the animal of PCC+Fib treatment, due to serious
DIC, 240 minutes after damaging at second, the concentration of fibrinogen is reduced to 114 ± 42mg/dL at any time.This fiber egg
Dramatically increasing for the consumption of white original and d-dimer is related.In Figure 10, the concentration of d-dimer whithin a period of time is presented
(average value ± standard deviation).After being transfused PCC, d-dimer increases immediately in PCC50 and PCC+Fib group, and these are horizontal
Continue to increase (240 minutes 249 ± 176mg/L of PCC50 group after damage for the second time within the entire observation period;PCC+Fib group 193 ±
180mg/L).In AT substitution group, d-dimer increases to lesser degree (240 minutes: PCC+AT50 group 27 after second of wound
±20mg/L;10 ± 7mg/L of PCC+AT25 group;14 ± 7mg/L of PCC+AT12.5 group;68 ± 79mg/L of PCC+Fib+AT50 group).
Figure 11 illustrates the data (average value ± standard deviation) that process at any time is generated about fibrin ferment.Receiving PCC
All animals in PCC application after, fibrin ferment generate immediately increase (PCC50 group 1448 ± 569nM x min;PCC50+Fib group
1601±972nM x min).In the animal for coming from PCC+Fib+AT50 (645 ± 286nM x min) and PCC+ antithrombase group
Middle addition antithrombase (PCC+AT50 group 769 ± 84nM x min;PCC+AT25 group 1084 ± 123nM x min;PCC+
AT12.5 group 1266 ± 126nM x min) cause the fibrin ferment of reduced levels to generate.Fibrin ferment generation in these animals is higher than
Control group (for example, 30 minutes: 275 ± 25nM × min after second of wound).Although in the animal that PCC replaces during observation
The generation of fibrin ferment is gradually reduced at any time, but the generation of fibrin ferment is still higher than baseline at 240 minutes after second of wound.
Figure 12 illustrates the data (average value ± standard deviation) about prothrombin time (PT) process at any time.Second
Because blood loss PT extended to 12.3 ± 2.0 seconds from 9.6 ± 0.8 seconds at any time after secondary injury.Receive the animal of PCC 50 at second
Damage is significant after sixty minutes to extend at most 149 ± 87 seconds at 240 minutes.PT in every other intervention group keeps steady at any time
It is fixed.Measurement aPTT observed similar discovery.
Figure 13 illustrates the data (average value about activated partial factor I time (aPTT) process at any time
± standard deviation).
Claims (24)
1. coagulation factor substitute products, it
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease;
The product includes at least isolated factor (factor II) and isolated Antithrombin III (ATIII), wherein
Molar ratio between ATIII and factor II is at least 1:30;
The wherein product described by application, reduces the risk of patient's thromboembolic complication.
2. the coagulation factor substitute products applied according to claim 1, wherein the product described by application, with reference therapy phase
Than the risk of patient's thromboembolic complication being reduced, in addition to the ATIII and factor II of product used in the reference therapy
Between molar ratio lower than other than 1:30, the reference therapy is identical as the treatment.
3. according to claim 1 or claim 2 apply coagulation factor substitute products, wherein the product also includes selected from the factor
At least one of the isolated coagulation factor of IX, factor X and factor Ⅴ II.
4. according to the coagulation factor substitute products that any one of the claims are applied, wherein with controlling after placebo treatment or not
The blood loss for the treatment of is compared, and is reduced with the blood loss of patient after product treatment, wherein blood loss is preferably decreased to placebo treatment
Rear blood loss or the blood loss that do not treat lower than 75%, lower than 70%, lower than 60%, lower than 55%, lower than 50%, it is low
In the 45%, amount lower than 40% or lower than 35%.
5. according to the coagulation factor substitute products that any one of the claims are applied, wherein being used when compared with reference therapy
The blood loss of patient is essentially identical after product treatment or only appropriateness increases, or wherein when compared with reference therapy, with this
The blood loss of patient is reduced after product treatment, it is preferable that when compared with reference therapy, with the blood loss of patient after product treatment
Amount reduces at least 5%, at least 10%, at least 15% or at least 20%, wherein in addition to product used in the reference therapy
For molar ratio between ATIII and factor II lower than other than 1:30, the reference therapy is identical as the treatment.
6. according to the coagulation factor substitute products that any one of the claims are applied, wherein in the blood loss phase with reference therapy
Than when under the blood loss of patient after product treatment only increased situation of appropriateness, the appropriateness, which increases to amount to, to be no more than
60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 15%, no more than 10% or do not surpass
Cross 5%, wherein in addition to the molar ratio between the ATIII and factor II of product used in the reference therapy lower than 1:30 with
Outside, the reference therapy is identical as the treatment.
7. according to the coagulation factor substitute products that any one of the claims are applied, wherein with controlling after placebo treatment or not
The time value for reaching hemostasis treated is compared, and is reduced with the time value for reaching hemostasis of patient after product treatment, wherein with comfort
Value or the value do not treated after agent treatment are compared, reach after the treatment with the product hemostasis time value be preferably reduced by it is few
25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% or at least 60%.
8. according to the coagulation factor substitute products that any one of the claims are applied, wherein being used when compared with reference therapy
The product treatment after patient the time value for reaching hemostasis it is substantially the same or only appropriateness increase, or in which with reference therapy phase
Than when, with the product treatment after patient reach hemostasis time value reduce, it is preferable that compared with the value after reference therapy, use
The time value for reaching hemostasis of patient is reduced at least 5%, at least 10%, at least 15% or at least 20% after product treatment,
In the product used in the reference therapy ATIII and factor II between molar ratio lower than other than 1:30, it is described
Reference therapy is identical as the treatment.
9. according to the coagulation factor substitute products that any one of the claims are applied, wherein being used when compared with reference therapy
The time value for reaching hemostasis of patient only moderately increases after product treatment, and the appropriateness, which increases to amount to, is no more than 80%, no
More than 70%, it is no more than 60%, is no more than 50%, is no more than 40%, is no more than 30%, being no more than 20% or be no more than 10%,
Wherein the molar ratio between the ATIII and factor II of the product used in the reference therapy is described lower than other than 1:30
Reference therapy it is identical as the treatment.
10. according to the coagulation factor substitute products that any one of the claims are applied, wherein the factor with reference therapy
Time (PT) value and/or activated partial factor I time (aPTT) value are compared, the trouble after with product treatment
Prothrombin time (PT) value and/or activated partial factor I time (aPTT) value of person reduce at least 1.5 times, extremely
2.0 times, at least 2.5 times, at least 3.0 times, at least 3.5, at least 4.0, at least 4.5, at least 5.0, at least 7 times or at least 10 less
Times, wherein other than the molar ratio between the ATIII of the product used in the reference therapy and factor II is lower than 1:30,
The reference therapy is identical as the treatment.
11. according to the coagulation factor substitute products that any one of the claims are applied, wherein with after placebo treatment or do not have
There are the analog value and/or the analog value of activated partial factor I time (aPTT) of the prothrombin time (PT) for the treatment of
Compared to when, the patient with the product treatment after prothrombin time (PT) value and/or activated partial thrombokinase original swash
Enzyme time (aPTT) value is substantially the same and/or maximum deviation with described value, and condition is that the maximum deviation is no more than
5.0 times, 3.0 times, 2.5 times, 2.0 times or 1.5 times.
12. according to the coagulation factor substitute products that any one of the claims are applied, wherein in the fibrin ferment with reference therapy
It generates, when the value that especially fibrin ferment generates potentiality (ETP) is compared, is generated with the fibrin ferment of patient after product treatment, especially
Be fibrin ferment generate potentiality (ETP) value reduce at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least
30%, at least 35%, at least 40%, at least 45% or at least 50%, wherein in addition to the product used in the reference therapy
ATIII and factor II between molar ratio lower than other than 1:30, the reference therapy is identical as the treatment.
13. according to the coagulation factor substitute products that any one of the claims are applied, wherein compared with reference therapy, with this
Product treatment after patient's blood d-dimer concentration (DD) value reduce at least 2 times, at least 3 times, at least 4 times, at least 5 times,
At least 7 times or at least 10 times, wherein in addition to mole between the ATIII and factor II of the product used in the reference therapy
Than lower than other than 1:30, the reference therapy is identical as the treatment.
14. according to any one of the claims apply coagulation factor substitute products, wherein the product also include heparin and/or
Albumin.
15. factor II is wherein provided in the product according to the coagulation factor substitute products that any one of the claims are applied,
Activity level is 10-80IU/mL, preferably 15-60IU/mL.
16. according to the coagulation factor substitute products that any one of the claims are applied, wherein rubbing between ATIII and factor II
You are than being not higher than 1:0.5, preferably no greater than 1:1.
17. according to the coagulation factor substitute products that any one of the claims are applied, wherein rubbing between ATIII and factor II
That ratio is in the range of 1:25 to 1:0.5, preferably 1:25 to 1:1.
18. according to the coagulation factor substitute products that any one of the claims are applied, wherein the treatment or prevention include
Bleeding in the acquired deficiency disease for the treatment of and peri-operation period prevention prothrombin complex coagulation factor, especially by vitamin
K antagonist for treating, or when needing quickly to correct the deficiency disease in the excessive situation of vitamin K antagon caused deficiency disease
In bleeding;Or wherein the treatment or prevention include that treatment and peri-operation period prevent any vitamin k-dependent blood coagulation
Bleeding in the congenital deficiency disease of the factor, especially the specific coagulation Factor products of purifying not using when.
19. according to the coagulation factor substitute products that any one of the claims are applied, wherein in addition to being treated with the product
Except, patient is also preparatory, subsequently or simultaneously uses substitute products, such as cold hypostasis, or is treated with fibrinogen concentrate, preferably
With between 5 mg/kgs and 150 mg/kg weight, between 10 mg/kgs and 100 mg/kgs, preferably 20
Substitute products or fiber described in fibrin commercial weight application between mg/kg and 80 mg/kg weight
Proteinogen concentrate.
20. wherein the product is the following two kinds type according to the coagulation factor substitute products that any one of claim 3-19 is applied
The prothrombin complex concentrate (PCC) of any one:
3 factor coniplexes of Coverage factor II, IX and X;Or
Additionally comprise 4 factor coniplexes of factor Ⅴ II;
The product additionally comprises Antithrombin III (ATIII), and wherein the molar ratio between ATIII and factor II is at least
1:30。
21. combination treatment, it includes application prothrombin complex concentrate (PCC) and combined administration Antithrombin III
(ATIII), the combination treatment
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease,
It is institute that the PCC, which includes at least factor (factor II), factors IX, factor X and optional Coverage factor VII, condition,
Molar ratio between the ATIII of application and the factor II applied is at least 1:30;And
The wherein combination described by application, reduces the risk of the thromboembolic complication of patient.
22. the drug coagulation factor of any one of -19 applications substitutes complete product according to claim 1, which includes:
(i) first chamber of factor (factor II) is included at least, and
(ii) comprising the second chamber of Antithrombin III (ATIII), wherein providing described first group in the complete product
Object and the second chamber are closed, to allow
(a) mixture is prepared before administration, which has the molar ratio between at least ATIII of 1:30 and factor II, with
And/or
(b) for being administered in combination the mixture or composition, condition be applied ATIII with the factor II that is applied it
Between molar ratio be at least 1:30, wherein the composition described by application, reduces the wind of the thromboembolic complication of patient
Danger.
23. drug products, it includes the Antithrombin III being administered in combination with the product comprising factor (factor II)
(ATIII), the drug products
(i) it is used to treat or prevent the patient's bleeding with acquired coagulation factor deficiency disease, or
(ii) for treating or preventing the patient's bleeding with coagulation factor congenital deficiency disease;
Factor (factor II) and Antithrombin III (ATIII) is wherein administered in combination, it have at least ATIII of 1:30 and
Factor II molar ratio;
Wherein by the way that the product is administered in combination, the risk of the thromboembolic complication of patient is reduced.
24. (i) treats or prevents the patient's bleeding with acquired coagulation factor deficiency disease, or (ii) is treated or prevented with first
The method of the patient's bleeding of nature deficiency of coagulation factors, by being applied described in the progress of coagulation factor substitute products to the patient
Treatment or prevention,
The product includes at least isolated factor (factor II) and isolated Antithrombin III (ATIII), wherein
Molar ratio between ATIII and factor II is at least 1:30;
The wherein product described by application, reduces the risk of the thromboembolic complication of patient.
Applications Claiming Priority (3)
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EP17155420 | 2017-02-09 | ||
EP17155420.7 | 2017-02-09 | ||
PCT/EP2018/053240 WO2018146235A1 (en) | 2017-02-09 | 2018-02-09 | A blood coagulation factor replacement product for use in the treatment or prophyl of bleedings |
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CN110114074A true CN110114074A (en) | 2019-08-09 |
CN110114074B CN110114074B (en) | 2024-05-28 |
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CN201880005539.2A Active CN110114074B (en) | 2017-02-09 | 2018-02-09 | Coagulation factor replacement product for treating or preventing bleeding |
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US (1) | US11744880B2 (en) |
EP (1) | EP3579857B1 (en) |
JP (1) | JP7227905B2 (en) |
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CN113929741A (en) * | 2020-06-29 | 2022-01-14 | 首都医科大学 | warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA 1 and synthesis, activity and application thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4663164A (en) * | 1980-01-28 | 1987-05-05 | Baxter Travenol Laboratories, Inc. | Aqueous compositions for treating blood clotting factor inhibitors |
US5866122A (en) * | 1996-03-20 | 1999-02-02 | Immuno Aktiengesellschaft | Pharmaceutical preparation for treating blood coagulation disorders |
US6346277B1 (en) * | 1983-10-08 | 2002-02-12 | Aventis Behring Gmbh | Process for the pasteurization of plasma or concentrates of blood coagulation factors II, VII, IX and X |
CN102459583A (en) * | 2009-06-05 | 2012-05-16 | 法国分馏学和生物学实验室 | Prothrombic complex composition |
WO2016198351A1 (en) * | 2015-06-10 | 2016-12-15 | Evonik Röhm Gmbh | Process for preparing a powder comprising a human coagulation factor protein and a lactic acid polymer |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3101752A1 (en) | 1981-01-21 | 1982-08-26 | Behringwerke Ag, 3550 Marburg | "METHOD FOR PURIFYING THE BLOOD COAGINING FACTORS II, VII, IX AND / OR X AND PREPARATIONS PRODUCED THEREFORE" |
DE3622642A1 (en) | 1986-07-05 | 1988-01-14 | Behringwerke Ag | ONE-COMPONENT TISSUE ADHESIVE AND METHOD FOR THE PRODUCTION THEREOF |
AT409334B (en) | 1997-09-19 | 2002-07-25 | Immuno Ag | PHARMACEUTICAL PREPARATION CONTAINING VITAMIN K-DEPENDENT INDIVIDUAL FACTORS |
US20040208786A1 (en) | 2003-01-27 | 2004-10-21 | Kevy Sherwin V. | Autologous coagulant produced from anticoagulated whole blood |
EP2624859B1 (en) | 2010-10-06 | 2017-03-01 | Medimmune Limited | Factor ii alone or in combination with further factors for treatment of impaired haemostasis associated with dilutional coagulopathy |
TWI653047B (en) | 2014-03-14 | 2019-03-11 | 百特製藥公司 | Composition of human prothrombin and activating factor X for promoting hemostasis in the treatment of hemorrhagic disorders |
-
2018
- 2018-02-09 KR KR1020197018871A patent/KR102658958B1/en active IP Right Grant
- 2018-02-09 CA CA3046406A patent/CA3046406C/en active Active
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- 2018-02-09 DK DK18703026.7T patent/DK3579857T3/en active
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4663164A (en) * | 1980-01-28 | 1987-05-05 | Baxter Travenol Laboratories, Inc. | Aqueous compositions for treating blood clotting factor inhibitors |
US6346277B1 (en) * | 1983-10-08 | 2002-02-12 | Aventis Behring Gmbh | Process for the pasteurization of plasma or concentrates of blood coagulation factors II, VII, IX and X |
US5866122A (en) * | 1996-03-20 | 1999-02-02 | Immuno Aktiengesellschaft | Pharmaceutical preparation for treating blood coagulation disorders |
CN102459583A (en) * | 2009-06-05 | 2012-05-16 | 法国分馏学和生物学实验室 | Prothrombic complex composition |
WO2016198351A1 (en) * | 2015-06-10 | 2016-12-15 | Evonik Röhm Gmbh | Process for preparing a powder comprising a human coagulation factor protein and a lactic acid polymer |
Non-Patent Citations (6)
Title |
---|
文圆等: "人凝血酶原复合物的研究进展", 《微生物学免疫学进展》 * |
文圆等: "人凝血酶原复合物的研究进展", 《微生物学免疫学进展》, no. 04, 20 August 2012 (2012-08-20) * |
曾戎 等: "《生物医用仿生高分子材料》", 31 October 2010, 华南理工大学出版社, pages: 115 * |
辛叶等: "PCC中不同水平抗凝血酶和肝素对其促凝及抗凝能力的影响", 《中国生化药物杂志》, no. 04, 28 April 2015 (2015-04-28) * |
陈梁军 等: "全国高职高专院校药学类与食品药品类专业十四五规划教材 生物制药工艺技术 供药品生产技术专业用 第2版", 中国医药科学技术出版社, pages: 590 * |
魏旭东等: "《血液病药物手册》", 31 May 2001, 人民卫生出版社, pages: 63 - 64 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113929741A (en) * | 2020-06-29 | 2022-01-14 | 首都医科大学 | warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA 1 and synthesis, activity and application thereof |
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CA3046406A1 (en) | 2018-08-16 |
WO2018146235A8 (en) | 2019-05-09 |
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